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Identification of Molecules Mediating Axonal Guidance using Model Systems
Screen for Mutantsof Neuronal Specificity
Clone Mutant Genes
Observe WTNeuronal Specificity
IdentifyFactors
(Semphorins, Slit,Robo, Commissureless...)
Conserved Structural Classes of Axonal Guidance
Molecules: Modular Construction and Multifunctionality
1. Laminin, fibronectin and extracellular matrix proteins.2. Cadherins and catenins. (Ca+2 dependent)3. Cell adhesion molecules (CAMs) (containing IgG domains).4. Receptor tyrosine kinases and receptor phosphatases.
Functional Classes of Axonal Guidance Molecules
(Secreted)
(Membrane Associated)
(netrin) (sema, slit)
(fas) (eph)
Molecules may function for both:1. Selective adhesion2. Intracellular signaling
Axonal Guidance Cues
selectivefasciculation
diffusibleattractant
diffusiblerepellant
Contact-dependentattractant
Contact-dependentrepellant
(Timing is critical)
Axonal Guidance
1. Pioneer neurons construct the earliest scaffold of the nervous system, following chemical cues.
2. Multiple chemical cues guide growth cones, including long-range diffusible cues (secreted molecules) and short-range contact mediated cues (membrane associated).
3. Chemical cues may be attractive or repulsive.
4. Chemical cues mediate both selective adhesion and intercellular signaling.
5. Axonal guidance molecules are ancient conserved molecules, including a large class with structural similarity to immunoglobulins.
6. Final axonal pathways likely specified by unique combinations of molecular cues expressed by growing neurons and targets (Sperry’s Chemoaffinity Hypothesis).
7. Human mutations of axonal guidance genes may underlie many hereditary neurological conditions affecting complex cognitive functions.
The Axon Guidance Receptor Gene ROBO1Is a Candidate Gene for Developmental Dyslexia
Katariina Hannula-Jouppi1, Nina Kaminen-Ahola1, Mikko Taipale1,2, Ranja Eklund1, Jaana Nopola Hemmi1,3,Helena Kaariainen4,5, Juha Kere1,6*
1 Department of Medical Genetics, University of Helsinki, Finland, 2 European Molecular Biology Laboratory, Gene Expression Programme, Heidelberg, Germany,3 Department of Pediatrics, Jorvi Hospital, Espoo, Finland, 4 Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland, 5 Department of Medical Genetics, University of Turku, Turku, Finland, 6 Department of Biosciences at Novum and Clinical Research Centre, Karolinska Institutet, Stockholm, Sweden
PLOS Genetics (2005) 1: 0467
Development Proceeds by ProgressiveDevelopmental Restrictions