From the Eye to the Brain: Development of the Drosophila Visual ...

From the Eye to the Brain:Development of the DrosophilaVisual SystemNathalie N�eriec*,†, Claude Desplan*,†,1*Center for Genomics & Systems Biology, New York University, Abu Dhabi, UAE†Department of Biology, New York University, New York, USA1Corresponding author: e-mail address: [email protected]

Contents

1. Introduction 22. The Drosophila Visual System 2

2.1 The Compound Eye 22.2 Optic Lobe 42.3 Visual Centers in the CB 7

3. Development of the Fly Visual System 73.1 The Retina 73.2 The Ventral Nerve Cord and CB 73.3 The Optic Lobe 73.4 Linking Development to Adult Fate 10

4. General Rules of Neuronal Development 124.1 Production of Neurons 134.2 Common Mechanisms for Neuronal Specification 14

5. Conclusions and Perspectives 165.1 Integration at the Molecular Level 175.2 Circuits and Retinotopy 175.3 Evolution 18

References 19

Abstract

How stem cells produce the huge diversity of neurons that form the visual system, andhow these cells are assembled in neural circuits are a critical question in developmentalneurobiology. Investigations in Drosophila have led to the discovery of several basicprinciples of neural patterning. In this chapter, we provide an overview of the fieldby describing the development of the Drosophila visual system, from the embryo tothe adult and from the gross anatomy to the cellular level. We then explore the generalmolecular mechanisms identified that might apply to other neural structures in flies or invertebrates. Finally, we discuss the major challenges that remain to be addressed in thefield.

Current Topics in Developmental Biology # 2016 Elsevier Inc.ISSN 0070-2153 All rights reserved.http://dx.doi.org/10.1016/bs.ctdb.2015.11.032

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http://dx.doi.org/10.1016/bs.ctdb.2015.11.032

1. INTRODUCTION

The mammalian brain is composed of a very large number of cells

belonging to many different cell types, a complexity that poses serious chal-

lenges (Kandel, Schwartz, & Jessell, 2000). Our current understanding of the

development of neural circuits underlying the computation of different

visual stimuli remains highly incomplete across species. Insects provide an

attractive model system since their nervous system is relatively simple, yet

the animals manifest very sophisticated visual behaviors (Collett, 2008;

Zeil, 2012).

How is neuronal diversity achieved during development of the visual

system?What are the genes and pathways defining large numbers of different

neuronal cell types? How are these cell types connected to form functional

circuits in the optic lobes? Thanks to the development of new molecular

genetic tools (del Valle Rodriguez, Didiano, & Desplan, 2012), significant

progress has been made toward understanding the development of the

Drosophila visual circuitry.

2. THE DROSOPHILA VISUAL SYSTEM

The adultDrosophila visual system contains�150,000 neurons and glia

cells (Chiang et al., 2011). Visual information is detected by the retina, while

visual processing occurs in the optic lobes that comprise more than 60% of

the brain’s neurons. The optic lobes are the major centers where neuronal

computations extract important features from the visual world, such as

shape, motion, color, e-vector orientation of polarized light, which are then

transmitted to the central brain (CB) (Fig. 1A–C;Borst&Helmstaedter, 2015;

Fischbach&Dittrich, 1989;Homberg,Heinze, Pfeiffer,Kinoshita,&el Jundi,

2011; Meinertzhagen & Hanson, 1993; Meinertzhagen et al., 2009; Otsuna,

Shinomiya, & Ito, 2014; Silies, Gohl, & Clandinin, 2014).

2.1 The Compound EyeThe adultDrosophila compound eye is made of�800 independent unit eyes

called ommatidia, corresponding to 800 pixels in the animal’s visual field.

Each ommatidium is composed of eight photoreceptor neurons that project

into the optic lobe. The organization of the eye will not be further described

here as it has been reviewed extensively in the recent past (Kumar, 2012;

Lamb, 2013; Paulk, Millard, & van Swinderen, 2011).

2 Nathalie N�eriec and Claude Desplan

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me

lop

lo la Eye

Optic lobeCentral brain Eye

A B

D

E

LC LT

VS

HS

VLNP

Mt

Tm

TmY

DmPm

Mi

Tlp/YT5 T4 La

R7

R1–R6

R8

C

VLNP

Figure 1 The visual system of Drosophila. (A) The fly brain in the head. (B) Neuropilsof the optic lobes and central brain. (C) Cross section of the fly brain indicating thedifferent parts of the visual system: eye, lamina (la), medulla (me), lobula (lo), lobulaplate (lop), and ventrolateral neuropils (VLNPs). (D) Interneurons of the optic lobe:outer and inner photoreceptors (pink (light gray in the print version)), lamina neurons

(Continued)

3Development of the Drosophila Visual System

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2.2 Optic LobeFly neurons are organized into approximately 50 areas composed mainly of

neuronal processes, called neuropils, with their cell bodies localized at the

periphery. Four of these neuropils form the optic lobe: lamina, medulla,

and the lobula complex which is further subdivided into the lobula and

the lobula plate neuropils (Morante & Desplan, 2004). Two major

types of neurons can be identified within the optic lobes: “interneurons”

whose cell bodies and projections remain within the optic lobe, and “pro-

jection” neurons, which connect the optic lobe to the CB (Fig. 1D and E;

Hofbauer & Campos-Ortega, 1990).

2.2.1 LaminaPhotoreceptors from each ommatidium involved in motion vision (outer

photoreceptors) first innervate the lamina neuropil, which manifests a

columnar organization in which each pixel of the visual field corresponds

to one cartridge (Meinertzhagen & Sorra, 2001). The lamina is mostly com-

posed of interneurons, whose projections do not leave the optic lobe with

their cell bodies located in the lamina cortex region. Lamina neurons can be

divided in two populations: Five types of monopolar neurons that contact a

single cartridge and project retinotopically into the medulla, and amacrine

cells that contact several cartridges within the lamina (Fischbach &

Dittrich, 1989; Hofbauer & Campos-Ortega, 1990; Tuthill, Nern, Holtz,

Rubin, & Reiser, 2013).

2.2.2 MedullaThe medulla neuropil receives direct innervation from color (inner) photo-

receptors, as well as from lamina monopolar neurons. The medulla neuropil

is stratified in 10 layers (M1–M10) with the region between layers M1 and

Figure 1—Cont'd (La, green (gray in theprint version)),medulla interneurons (dark blue(dark gray in the print version)), distal (Dm) and proximal medulla (Pm); medulla intrinsic(Mi); unicolumnar transmedullary (Tm) or multicolumnar TmY; lobula plate interneurons(T4, T5, Tlp, and Y neurons, dark brown (dark gray in the print version)). (E) Projectionsneurons: medulla tangential (Mt, dark blue (dark gray in the print version)); lobula colum-nar (LC, red (dark gray in the print version)) and tangential/tree-like (LT, red (dark gray inthe print version)); lobula plate tangential cells: HS and VS (dark brown (dark gray in theprint version)). Panel (A) adapted from Spalthoff, Gerdes, and Kurtz (2012). Panel (B) fromKrzeptowski et al. (2014). Panels (D and E) adapted from Erclik, Hartenstein, McInnes, andLipshitz (2009).


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M6 referred to as “distal medulla” that receives these external inputs

(Fischbach & Dittrich, 1989; Morante & Desplan, 2008; Takemura, Lu,

& Meinertzhagen, 2008). The “proximal medulla” (layers M7–M10)

receives information from the distal medulla and further computes visual

information. Themedulla neuropil is organized in repetitive columnar units,

oriented perpendicular to the 10 layers that are reminiscent of lamina car-

tridges (Fischbach & Dittrich, 1989). Retinotopic connections between

medulla columns, photoreceptors, and lamina cartridges ensure an accurate

representation of the visual world (Chin, Lin, Fu, Dickson, & Chiang, 2014;

Fischbach & Dittrich, 1989; Meinertzhagen & Sorra, 2001; Morante &

Desplan, 2008; Zhu, 2013).

The serpentine layer, which separates the distal and proximal medulla,

consists of incoming and outgoing axons of projection neurons, which all

connect to more than one medulla column. Different types of projection

neurons can be identified based on the location of their cell bodies, their

dendritic morphology, and their axonal projection patterns (Fischbach &

Dittrich, 1989; Strausfeld, 1989), but the functional contribution of most

of these neurons remains unclear.

The medulla contains about 40,000 interneurons, representing the larg-

est neuronal subpopulation in the optic lobe (Fischbach & Dittrich, 1989).

Their cell bodies are located either within the medulla cortex between the

lamina and the medulla neuropils, or within the medulla rim, located below

the medulla neuropil near the lobula complex (Bausenwein, Dittrich, &

Fischbach, 1992; Fischbach & Dittrich, 1989). Medulla interneurons have

been extensively characterized and categorized in over 80 cell types, first

by Cajal and Sanchez (1915), followed by Fischbach and Dittrich (1989),

and more recently by Morante and Desplan (2008), Raghu, Claussen,

and Borst (2013), Raghu, Joesch, Sigrist, Borst, and Reiff (2009), and

Varija Raghu, Reiff, and Borst (2011). They can be subdivided into subcat-

egories based on their projections patterns (Fig. 1D): Interneurons that

project over a large visual field, across many columns, are called tangential

(Dm and Pm in Fig. 1D). Columnar neurons projections are mainly parallel

to the medulla columns (Mi, Tm, and TmY in Fig. 1D). They can be uni-

columnar and project within a single medulla column, suggesting that they

process information from one visual point in space, or multicolumnar with

projections spanning several medulla columns. Only columnar neurons pro-

ject outside the medulla into the lobula and lobula plate, which represent

the main output of the medulla neuropil (Fischbach & Dittrich, 1989;

Morante & Desplan, 2008).


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2.2.3 Lobula Complex: The LobulaThe lobula can be divided into six layers arranged perpendicularly to the

columnar structures resulting from the columnar inputs of the medulla neu-

rons (Fischbach & Dittrich, 1989). Almost all lobula cells are projection

neurons whose cell bodies are located between the CB and the lobula neu-

ropil. Interestingly, despite the cell bodies’ varying distance to the lobula,

their projections all merge at the neck of the lobula to form a single fiber

tract connecting the lobula to the CB (Fig. 1E; Otsuna & Ito, 2006). Lobula

neurons can be divided into two categories: Columnar neurons (LC) receive

visual input from 8 to 9 ommatidia (Douglass & Strausfeld, 2003; Mu, Ito,

Bacon, & Strausfeld, 2012; Otsuna & Ito, 2006), reminiscent of multicol-

umnar neurons in the medulla; tangential- and tree-like neurons (LT)

receive input from very large visual fields, similar to medulla tangential

neurons (Otsuna & Ito, 2006; Fig. 1E).

2.2.4 Lobula Complex: The Lobula PlateRepresenting the output center of the neural circuits that process motion,

the lobula plate neuropil can be divided in four layers containing dendrites

that each manifest maximal sensitivity to motion along one of the four car-

dinal directions (front-to-back, back-to-front, up, and down) (Fischbach &

Dittrich, 1989; Maisak et al., 2013). Two classes of lobula plate interneurons

called T4 and T5 cells can each be further subdivided into four subclasses

forming dendrites in only one of the four specific layers (hence termed

T4a, b, c, d and T5a, b, c, d). Their role in motion detection has been studied

and was reviewed in Behnia and Desplan (2015) and Borst and Helmstaedter

(2015). Their cell bodies are all located adjacent to the lobula plate neuropil,

underneath medulla rim cell bodies (Fig. 1C). Two other classes of interneu-

rons have presynaptic input in the lobula plate and postsynaptic output in the

lobula: the translobula plate neurons (Tlp) and Y cells. Both have their cell

bodies adjacent to those of T4 and T5 cells. As observed in larger flies, only

few intrinsic cells, i.e., which remain within the lobula plate neuropil, can be

observed (Fischbach & Dittrich, 1989).

The lobula plate tangential cells (LPTCs) are projection neurons whose

characterization has provided great insight into the computation of motion

(Hausen, 1984; Maisak et al., 2013). In general, LPTCs are sensitive to visual

motion in a direction-selective manner (Hausen, 1984). Historically, the

most extensively studied LTPCs belong to the horizontal (HS) and vertical

(VS) system (Fig. 1E; Borst & Haag, 2002). They receive their inputs from

the T4 and T5 neurons and transmit direction-selective visual information


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to the ventrolateral neuropils (VLNPs) of the CB (Behnia & Desplan, 2015;

Borst, 2014; Borst & Haag, 2002; Silies et al., 2013).

2.3 Visual Centers in the CBThe VLNPs (also called optic glomeruli) are located right underneath the

optic lobes and can be considered the next step in visual processing after

the optic lobes. All 14 different types of lobula projection neurons project

to distinct target regions within the VLNPs (Otsuna & Ito, 2006). They each

project into the VLNP as one single bundle in a way reminiscent to olfactory

glomeruli (Mu et al., 2012; Otsuna & Ito, 2006). The availability of highly

specific Gal4 lines that label most of the optic lobe cell types (Jenett et al.,

2012; Li et al., 2014; Pfeiffer et al., 2008) should allow the determination

of the visual function performed by each optic glomerulus (Aptekar,

Keles, Lu, Zolotova, & Frye, 2015; Mu et al., 2012).

3. DEVELOPMENT OF THE FLY VISUAL SYSTEM

3.1 The RetinaThe development of the fly retina is one of the best-understood complex

structures. It has been reviewed in many articles (Carthew, 2007; Kumar,

2012; Treisman, 2013) and will not be described further in this review.

3.2 The Ventral Nerve Cord and CBThe ventral nerve cord (VNC) and CB are generated in the embryo from

neuroblasts delaminating from the embryonic neuroepithelium. These neu-

roblasts produce the embryonic nervous system and 10% of the future adult

neurons before entering quiescence toward the end of embryonic stages

(Fig. 2A). At late L1/early L2 stages, about 100 neuroblasts start dividing

again and produce the remaining 90% of adult neurons. The neuroblasts

can be divided in two categories: Type I neuroblasts generate all VNC neu-

rons and most of the CB, while eight Type II neuroblasts generate clones of

up to 500 cells giving rise to CB neurons. The formation of neurons from

the VNC/CB neuroblasts has been recently reviewed in Homem and

Knoblich (2012), Kang and Reichert (2015), and Reichert (2011).

3.3 The Optic LobeThe optic lobe is derived from cells located in the posterior part of the

embryonic head (Green, Hartenstein, & Hartenstein, 1993; Nassif et al.,


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L1 L2

Proliferation

Delamination

Quescience Type II

Type I

L3 Pupa

A

b c d e f

B

OPC

IPCLa

Pr

vtIPC

C

a g

dIPCMe

Pr

La

Me

dIPC

Figure 2 The development of the optic lobe ofDrosophila. (A) Central brain: neuroblasts(green (light gray in the print version)) delaminate from the neuroepithelium (red(dark gray in the print version)) during the embryonic stages and generate GMCs(purple (dark gray in the print version)) and larval neurons (blue (gray in the printversion)) before they become quiescent. At L1, Type I and Type II neuroblasts arereactivated and exhibit different modes of proliferation to generate adult neurons.(B) Optic lobe: (a) Cells in the procephalic regions generate the optic placode neuro-epithelium (red (dark gray in the print version)), which invaginates (b). (c) The opticplacode splits into inner proliferation center (IPC, pink (gray in the print version)) andouter proliferation center (OPC, blue (dark gray in the print version)) and adopt a cres-cent shape (d). (e) Cells migrate out of the IPC to form the dIPC (light brown (light gray inthe print version)). (f ) The medial edge of the OPC becomes neuroblasts that will pro-duce the medulla (round blue (dark gray in the print version) cells). (g) The inner OPCgenerates lamina progenitors (La, green (light gray in the print version)) that will pro-duce lamina neurons upon induction by photoreceptors (Pr, pink (gray in the print ver-sion) arrows). The ventral tip of the IPC generates lobula complex neurons (vtIPC, darkyellowish green (gray in the print version)). Lower diagrams are cross sections at thedashed line in upper diagrams. (C) 3D representation of the brain at L3. Central brainneuroblasts and their progeny, OPC (blue (dark gray in the print version)) and IPC (pink(gray in the print version)). The eye symbol shows the view angle of panel (B). Panels (Aand C) adapted from Homem and Knoblich (2012)). Panel (B) adapted from Nassif, Noveen,and Hartenstein (2003).


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2003). During the same time windowwhen neuroblasts of the VNC andCB

delaminate, optic lobe precursor cells undergo four rounds of mitosis to form

a plate-like structure that is made of densely packed columnar cells called

optic placode (Green et al., 1993; Fig. 2Ba). After the fourth division, the

cells of the developing optic lobe remain mitotically quiescent throughout

the rest of embryogenesis (Green et al., 1993).

After all neuroblasts of the CB have delaminated from the head ecto-

derm, the optic lobe placode becomes attached to the ventrolateral surface

of the brain and invaginates by apical constriction. During this invagination

process, the placode adopts a V-like shape, with an anterior and a posterior

tip (Green et al., 1993; Hofbauer & Campos-Ortega, 1990; White &

Kankel, 1978; Fig. 2Bc).

Uponhatching of the first instar larva, a small groupof cells at the anterior-

dorsal tip of the optic placode detaches, splitting the developing optic

lobe into two, creating the outer proliferation center (OPC) and the inner

proliferation center (IPC) (Meinertzhagen & Hanson, 1993; Nassif et al.,

2003; Younossi-Hartenstein, Nassif, Green, &Hartenstein, 1996; Fig. 2Bd).

Toward the end of the second larval instar, the OPC and the IPC

both adopt a crescent shape, with the opening of the crescent pointing

posteriorly (Fig. 2Bd). Both OPC and IPC anlagens remain in contact with

each other until the end of the second instar, when they become separated

by newly generated cells that penetrate into the space between the IPC and

the OPC (Fig. 2Be). These cells migrate in from the IPC to form a distant

proliferative center called the dIPC. The ventral tip of the IPC also prolif-

erates and generates neurons (Apitz & Salecker, 2015; Hofbauer & Campos-

Ortega, 1990; Neriec et al., Submitted).

From the end of the second instar onward, cells at the medial edge of the

OPC neuroepithelium crescent begin to lose their columnar shape and

adherens junctions without delaminating (Fig. 2Bf ). They are converted

into neuroblasts in a moving proneural wave (reviewed in Apitz &

Salecker, 2014). These medulla neuroblasts divide asymmetrically to self-

renew and generate their progeny composed of neurons and glia (Egger,

Boone, Stevens, Brand, & Doe, 2007). By 20 h after puparium formation

(APF), �40,000 neurons have been generated, most of which will become

medulla cortex neurons (Egger, Gold, & Brand, 2010, 2011).

During the third larval instar, a second proliferation zone develops at the

opposite edge of the OPC. This second zone is separated from the future

medulla neuroblast by the deep lamina furrow (Fig. 2Bg). By mid-third

instar, photoreceptor axons start to project into the developing optic lobe


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via the optic stalk (pink (gray in the print version) arrow in Fig. 2Bg). Lamina

neurons are produced and differentiate in response to Hedgehog (Hh) and

EGF produced by photoreceptors axons (Huang & Kunes, 1996, 1998;

Huang, Shilo, & Kunes, 1998; Selleck, Gonzalez, Glover, & White,

1992). By 25 h APF, it has generated about 6000 additional cells that

become lamina neurons and glia (Apitz & Salecker, 2014). The development

of theOPC,which generates the lamina and themedulla, has been studied in

much detail, while the development of the IPC, which generates the lobula

and lobula plate, has only recently been the topic of investigations (Apitz &

Salecker, 2015; Neriec et al., Submitted).

Starting around 25 h APF, the developing medulla starts to rotate, being

pulled by the lamina (Langen et al., 2015; White & Kankel, 1978), and

inserting itself right under the lamina neuropil. By 40 h APF, the rotation

is complete and the optic lobe has adopted its final configuration which

the four neuropils: lamina, medulla, lobula, and lobula plate (C. Bertet

and K. Fischbach, Personal communications).

3.4 Linking Development to Adult FateDue to the extreme morphological changes shaping the optic lobe during

pupation, the task of linking cell fates between larval and adult neurons

remains incomplete. Within the OPC, the cellular mechanisms that lead

to the formation of lamina precursor cells, the induction of their differenti-

ation into laminar monopolar neurons by the photoreceptors and their con-

nections have been well studied (Dearborn &Kunes, 2004; Huang &Kunes,

1996, 1998; Kunes, Wilson, & Steller, 1993). However, how the specifica-

tion of the five different types of lamina monopolar neurons is achieved

remains unknown. The rest of theOPC has been shown to generate medulla

cell types as well few lobula and lobula plate neurons (Fig. 3; Bertet et al.,

2014). General mechanisms used to specify different types of neurons have

been identified by Bertet et al. (2014), Erclik et al. (Under Review),

Hasegawa, Kaido, Takayama and Sato (2013), Li, Erclik, et al. (2013),

Sato, Suzuki, and Nakai (2013), and Suzuki, Kaido, Takayama, and Sato

(2013). A recent study has characterized some of the genetic mechanisms

involved in the generation of neurons of the lobula plate and medulla rim

from the main part of the IPC (Apitz & Salecker, 2015; Neriec et al.,

Submitted). Common mechanisms involved in the generation of neuronal

diversity have been identified in the optic lobe, the VNC and the CB. They

are similar in many regards to those observed in vertebrates and are detailed

in Section 4 of this review.


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The optic lobe projection neurons, including the lobula columnar

neurons (LCNs) and the LPTCs, as well as the CB neurons of the ven-

trolateral neuropils are believed to originate mostly from CB neuroblasts.

Recent studies have taken advantage of the fact that CB neurons remain

close to their birth place and generate reproducible series of neu-

ronal cell fates that represent the clonal units generated from each of

the 100 neuroblasts in the CB (Chiang et al., 2011; Ito, Masuda,

Shinomiya, Endo, & Ito, 2013; Lovick et al., 2013; Wong et al., 2013;

Yu et al., 2013) including intermediate progenitors of Type II neuroblasts

(Wang, Yang, et al., 2014).

Thirteen clonal units of neurons projecting into the optic lobe but also

into the CB have been described (Ito et al., 2013). These neurons all project

into the VLP where they form distinct nonoverlapping bulbous masses

corresponding to functionally relevant optic glomeruli: Neurons originating

from the same neuroblast clone share common projection pattern into spe-

cific glomeruli, which is indicative of functional similarities (Otsuna & Ito,

2006). This hints toward a direct link between the developmental origin of

projection neurons and their adult function. Similarities between the func-

tional connectivity of VLP and olfactory glomeruli have been pointed out

(Mu et al., 2012). Extensive work has been undertaken in order to under-

stand the formation of the olfactory glomeruli (for review, see Imai, Sakano,

& Vosshall, 2010), and similar future studies on the development of the optic

glomeruli will determine if similarities exist between the development of

these glomeruli.

CBPr

CB

Pr

vtIPC

La

Me

dIPC

Me

Lop

LaLo

A B

Figure 3 Linking development to adult fate. Fate of the different neuronal populationsfound at the L3 larval stage (A) in the adult visual system (B). Pr, photoreceptors; La,lamina; Me, medulla; Lo, lobula; Lop, lobula plate; dIPC, distal IPC; vtIPC, ventral tip ofthe IPC; CB, central brain.


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4. GENERAL RULES OF NEURONAL DEVELOPMENT

The generation of an adult neuron can be described in two main steps.

First, neurons are produced by neuronal stem cells. Then, once produced,

the prespecified neurons form axonal and dendritic projections and inte-

grate into developing neural circuits (Fig. 4A). We will review the general

Neuroepithelium Neuroblasts GMCsPostmitotic

neurons

B�. Spatial patterning B�. Temporal series B�. Binary cell choice

Vsx

Optix

Optix

HthEy Slp D Tll

NON

NOFF

NON

NOFF

E-Cadhpolarized,

tight junctionsDpnAse*

ProsAse

EMT-likeN, AS’c genes

Asymmetric division

B

A

Figure 4 The making of a functional neuronal network. (A) Common mechanisms forneurogenesis: polarizedneuroepithelial cells (red (darkgray in theprint version)) undergoEMT-like transition to become neuroblasts (green (light gray in the print version)) whichgenerate GMCs (purple (gray in the print version)). GMCs produce postmitotic neurons(blue (light gray in the print version)) that form adult neuronal circuits. * Dpn is foundin all neuroblasts while Ase is found in most neuroblasts (see text). (B) Commonmechanisms to generate neuronal diversity: (B0) Spatial patterning of the neuro-epithelium illustrated by the expression of Optix and Vsx (Gold & Brand, 2014). (B00)Temporal patterning of neuroblasts. In the OPC, neuroblasts sequentially express a seriesof transcription factors, Hth (red (gray in the print version)), Ey (blue (gray in theprint version)), Slp (green (dark gray in theprint version)), D (orange (light gray in theprintversion)), and Tll (cyan) as they age (arrows) (Li, Chen, & Desplan, 2013; Li, Erclik, et al.,2013). (B000) Notch-dependent binary cell fate choices during the division of GMCs. Onlyone of the two daughter cells (red (gray in the print version) clone, dashed line) receivesNotch activity and expresses Apterous (green (light gray in the print version)), while theother does not (Li, Chen, et al., 2013; Li, Erclik, et al., 2013).


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mechanisms of neurogenesis observed during the production (Section 4.1)

and the prespecification (Section 4.2) of optic lobe neurons and compare

them with the development of the CB.

4.1 Production of Neurons4.1.1 Generating Neuroblasts from a NeuroepitheliumBoth the Drosophila VNC/CB and the optic lobes are generated from cells

with epithelial-like characteristics; they are organized as monolayers with

cell of rectangular shapes connected by adherens junctions. These cells

express high levels of DE-Cadherin (E-Cadh) and manifest apicobasal

polarity (Acloque, Adams, Fishwick, Bronner-Fraser, & Nieto, 2009;

Doe, 1996).

In the embryonic neuroepithelium, one cell is stochastically singled-out

from 6 to 8 neuroepithelial cells via lateral inhibition mediated by Notch.

This cell expresses the highest level of AS-C genes and loses its connections

to its neighbors as well as with the apical surface just before delaminating and

becoming a neuroblast (for review, see Sanes, Reh, & Harris, 2012).

In the OPC, the transition of neuroepithelial cells into neuroblasts occurs

in a proneural wave, without the cells undergoing cell movement or delam-

ination: Cells in front of the wave are still neuroepithelial, while cells in the

wake of the proneural wave have become neuroblasts. The AS-C protein

L(1)sc is expressed in the transition zone between neuroepithelium and neu-

roblasts and, along with Notch, is necessary for the proneural wave (Apitz &

Salecker, 2014; Egger et al., 2007, 2011; Yasugi, Umetsu, Murakami, Sato,

& Tabata, 2008). In the IPC, cells undergo EMT and delaminate to later

become neuroblasts after migration to the dIPC, most likely also under

the control of L(1)sc and Notch (Apitz & Salecker, 2015; Neriec et al.,

Submitted). Further investigations are needed to determine in more details

the mechanisms by which L(1)sc and Notch control the timing of neuro-

epithelium to neuroblast transition in the optic lobe (Egger et al., 2011;

Yasugi, Sugie, Umetsu, & Tabata, 2010).

4.1.2 Generating Neurons from NeuroblastsNew generated neuroblasts undergo asymmetric division which results in

one replacement neuroblast and one GMC, which then divides once, gen-

erating two postmitotic cells, either neurons or glia. This is the case for 90%

of VNC and CB neuroblasts, called Type I neuroblasts, and for most neu-

roblasts of the OPC. The molecular mechanisms involved in such divisions

from the neuroblast to the GMCs have been well characterized and

reviewed in Homem and Knoblich (2012), Kang and Reichert (2015),


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and Sousa-Nunes and Somers (2013). Importantly, neuroblasts express

Deadpan (Dpn), GMCs express Prospero (Pros), and both express Asense

(Ase) (Brand & Livesey, 2011; Egger, Chell, & Brand, 2008; Egger et al.,

2011; Reichert, 2011; Southall & Brand, 2009;Wu, Egger, & Brand, 2008).

In recent years, examples that differ from such classic models have been

characterized. During CB neurogenesis, eight specialized Type II neuro-

blasts undergo asymmetric division to produce intermediate neural pro-

genitors instead of GMCs. These intermediate neural progenitors then

divide asymmetrically several times to replace themselves and generate

one GMC, leading to lineages that produce a large number of neurons

(Bayraktar, Boone, Drummond, & Doe, 2010; Bello, Izergina, Caussinus,

& Reichert, 2008; Boone & Doe, 2008; Bowman et al., 2008; Koe et al.,

2014; Viktorin, Riebli, & Reichert, 2013; Wallace, Liu, & Vaessin,

2000). Other neuroblasts (Type 0) of the CB and of the optic lobe generate

GMCs that do not divide but instead differentiate directly into one neuron

(or glia) (Baumgardt et al., 2014; Bertet et al., 2014). Recently, neuroblasts

generated by the IPC have been characterized and display atypical features

compared to other neuroblasts. First, they migrate between their delamina-

tion from the neuroepithelium and their arrival in the dIPC as atypical divid-

ing neuroblasts. Furthermore, these neuroblasts express Ase but not yet Dpn

and divide. Finally, they downregulate Ase as they age, thus lacking Ase

expression in their GMC progeny (Apitz & Salecker, 2015; Neriec et al.,

Submitted). Further studies remain necessary to characterize how those dif-

ferences play a role in the formation of neurons.

4.2 Common Mechanisms for Neuronal SpecificationNeuronal cell types can be defined based on cell morphology, cell connec-

tivity, marker expression, or intrinsic properties such as electrophysiological

properties. The specification of neuronal identity occurs in three main steps

(Lin & Lee, 2012): (a) spatial patterning of the neuroepithelium, (b) temporal

patterning of neuroblasts by series of transcription factors, (c) distinct hemi-

lineages from GMCs (Fig. 4B).

4.2.1 Spatial Patterning of the NeuroepitheliumThe first mechanism to specify different neuronal identities occurs in the

neuroepitheliumwhere spatial patterning cues exist early on. A classic exam-

ple is the fly embryo, where positional cues are provided by dorsoventral and

anteroposterior patterning genes: Gap genes and segment polarity, as well as


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dorsoventral and Hox genes establish a molecular coordinate system

(Technau, 2008; Urbach & Technau, 2003). Such Cartesian grid provides

a specific identity to any delaminating neuroblast, and this determines the

type of neurons that will be produced (Skeath, 1999; Skeath & Thor,

2003; Technau, Berger, & Urbach, 2006). In the OPC of the optic lobe,

the neuroepithelium crescent is also regionalized (Fig. 4B0): The tips of

the crescent express Wingless (Wg), which are bordered by a region

expressing decapentaplegic (Dpp), and together these two regions express

Rx, followed by an Optix region and finally a Vsx-1 expressing region in

the center (Erclik et al., Under Review; Gold & Brand, 2014).

Neuroblasts and some of the neurons they produce retain the positional

markers of the neuroepithelium in the different regions they are coming

from. This can affect their mode of neurogenesis. For instance, young neu-

roblasts of theWg region of the OPC do not generate classical Type I like in

the rest of the OPC, but instead become Type 0 and generate GMCs that

directly differentiate into one neuron (Bertet et al., 2014). More impor-

tantly, it ultimately affects the identity of the neurons that are being pro-

duced (Bertet et al., 2014; Erclik et al., Under Review). For instance,

Pm1 and Pm2 neurons are only generated from the Rx regions of the

OPC (Erclik et al., Under Review).

4.2.2 Temporal Patterning of NeuroblastsThe second mechanism by which neuronal diversity is generated temporal

patterning of neuroblasts as well as intermediate neuronal progenitors for Type

II neuroblasts: These cells sequentially express stereotyped temporal series of

transcription factors (reviewed in Li, Chen, et al., 2013; Fig. 4B00). These fac-tors are often transmitted to the postmitotic neurons, affecting the adult iden-

tity of the neuronal progeny (Bayraktar et al., 2010; Bertet et al., 2014; Isshiki,

Pearson, Holbrook, & Doe, 2001; Li, Erclik, et al., 2013). Despite differences

in the transcription factor repertoire used in these temporal series, the general

mechanism is very similar: One transcription factor not only induces expres-

sion of the next but also represses expression of the previous; changes in tran-

scription factor expression are correlated with changes in adult neuronal

progeny (Apitz & Salecker, 2014; Li, Chen, et al., 2013). Studies in vertebrates

seem to indicate that similar temporal series also play an important role in

mammalian neurogenesis, including the mouse retina (Livesey & Cepko,

2001; Mattar, Ericson, Blackshaw, & Cayouette, 2015; Wang, Sengel,

Emerson, & Cepko, 2014).


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4.2.3 Hemilineages from the GMCsFinally, a last source of neuronal diversity arises from molecular asymmetry

in the final division of GMCs: Indeed, both in the VNC/CB and during

optic lobe neuronal development, each GMC generates two postmitotic

cells that receive different levels of the protein Numb, a repressor of Notch

signaling. This creates two postmitotic cells with different Notch pathway

activity status: NotchON or NotchOFF (Fig. 4B000). These two groups of

neuroblast progeny are called hemilineages and differ in their adult neuro-

nal identity (Bertet et al., 2014; Lin, Kao, Yu, Huang, & Lee, 2012; Udolph,

2012).

In conclusion, spatial patterning in the NE, temporal series of transcrip-

tion factors in the neuroblasts, and GMC hemilineages define three main

axes through which neuronal diversity is generated (Lin & Lee, 2012).

Furthermore, different combinations of transcription factors have also been

shown to control cell death or survival (Bertet et al., 2014). For example, in

the optic lobe, NotchON neurons generated from the Wg region of the

neuroepithelium undergo apoptosis when they are generated in the time

window when the neuroblasts express the transcription factor Eyeless.

However, neurons emerging from the same neuroblasts, but during the

following Sloppy-paired time window, always survive when they are

NotchON but die when they are NotchOFF. These cells then adopt specific

adult identities (Bertet et al., 2014). In spite of the contribution of spatial

and temporal transcription factors, the general rules that dictate the forma-

tion of specific adult neuronal morphologies, interneurons versus projection

neurons, for example, remain completely unknown.

5. CONCLUSIONS AND PERSPECTIVES

Since the first description by Cajal over 100 years ago, the fly visual

system has been one of the most important models in developmental neu-

robiology. Progressing from the eye to the brain, a clearer picture emerges

regarding not only the connectome and the processing of visual information

in the fly brain but also the formation of neurons and establishment of such

network during development. Among the remaining studies to be done,

three main areas emerge of major interests: The integration of the neuronal

specification identities at themolecular level, themechanisms bywhich neu-

rons integrate within a neuronal circuits and finally the level of evolutionary

conservation between insects and human visual systems.


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5.1 Integration at the Molecular LevelAlbeit cellular mechanisms remain to be elucidated, such as the detailed

correlation of larval cell identities to adult neuronal types, developmental

studies of the fly visual system already have provided a blueprint for reaching

an understanding of this complex process at a molecular level. What are the

molecular mechanisms that control the integration of the three axes of

neuronal specification (spatial patterning of the neuroepithelium, window

of the temporal series of transcription factors and Notch status) for the

expression of specific terminal differentiation genes? Recently, the modules

that control the expression of a terminal differentiation gene such as the

neurotransmitter V-GLUT have been addressed in C. elegans (Serrano-

Saiz et al., 2013). What are the modules involved in Drosophila? Future

genomic and genetic studies will bring great insights in the mechanisms that

control the expression of late terminal differentiation genes in large and

complex neuronal circuits such as Drosophila.

Furthermore, the production of neurons from induced pluripotent stem

cells offers one of the most promising therapeutic approaches for the treat-

ment of neurodegenerative disorders (Hallett et al., 2015; Liu & Zhang,

2011). Adult human cells can already be induced into neuronal stem cells

and generate neurons in vitro that have been successfully transplanted in liv-

ing animals. However, the similarities and differences between in vitro-gen-

erated neurons and the in vivo neurons they would replace are a major

concern. To address this question, Drosophila offers a valuable model to

understand the molecular mechanisms involved in the formation of a neu-

ronal identity and the role of extrinsic versus intrinsic cues. For example,

experiments have shown that Type I neuroblasts from the CB still undergo

temporal series when cultivated in vitro (Grosskortenhaus, Pearson,

Marusich, & Doe, 2005). Similar experiments still remain to be done for

other type of neuroblasts, Type II and from the optic lobe.

5.2 Circuits and RetinotopyWhile some aspects of neuronal connections have been identified in the

formation of the visual system (Lee et al., 2003; Lee, Herman, Clandinin,

Lee, & Zipursky, 2001; Sanes & Zipursky, 2010; Timofeev, Joly,

Hadjieconomou, & Salecker, 2012), the establishment of connectivity

remains largely unknown. A major concept in visual system circuit forma-

tion is retinotopy, i.e., the topographic mapping of visual inputs from the

retina to optic lobe neurons. Retinotopy starts from the �800 ommatidia


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in the eye, each pointing to one point in space and projecting into an equiv-

alent number of cartridges in the lamina, which are therefore representing

the same points in space. Similarly, lamina neurons project into �800 col-

umns of the medulla, in an orderly fashion. Such conservation in the repre-

sentation of visual information is crucial for any visual system to be able to

extract information such as motion and is established very early during

development. Due to the direction in which the morphogenetic furrow

progresses, lamina neurons acquire their posterior-to-anterior identity based

on their time of differentiation. Retinotopy along the dorsoventral axis is

also preserved, when rows of photoreceptors generated at a given time point

contact developing lamina neurons, thereby forming cartridges. Therefore,

time represents an essential component in the generation of retinotopy, with

the induction of the lamina by the photoreceptors representing the critical

aspect.

However, how retinotopy is established in the medulla and in the higher

processing centers during development remains to be further investigated

since photoreceptors do not contribute to generating medulla or lobula

complex neurons.

5.3 EvolutionThe studies described here have generated broad concepts that start to apply

to vertebrate neurogenesis. Whether there is a common ancestry of insect

and vertebrate nervous systems is a major question in evolutionary biology

(Moroz, 2009). Today, the consensus converges toward the concept of a

common neuronal origin between flies and vertebrates (Strausfeld, 2009;

Strausfeld & Hirth, 2013a, 2013b; Wolff & Strausfeld, 2015), yet little is

understood about how much is shared between visual processing systems

in terms of development.

To address which features of the fly and vertebrate visual system may

have been present in their bilaterian ancestor, comparisons must be made

at the anatomical and functional levels (Erclik et al., 2009; Sanes &

Zipursky, 2010). However, while similarities between two adult visual sys-

tems might very well be due to evolutionary homology, they could also be

the result of convergent evolution due to physical constraints on the neuro-

nal circuits processing visual information (Strausfeld &Hirth, 2013a, 2013b).

Programs involved in the formation of neuronal circuits are under

specific developmental constraints and adult systems that arise from


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similar developmental programs are more likely to share a common origin.

The observed similarities in adult neuronal systems, likely mirroring similar-

ities in developmental programs, strongly suggest a common origin. As one

of the best-understood neuronal system, in flies and in vertebrates, the visual

system is well suited to address the question of homology between flies and

mammals (Erclik et al., 2009; Sanes & Zipursky, 2010) (_ENREF_92,

_ENREF_48).

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From the Eye to the Brain: Development of the Drosophila Visual ...

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