Outline of Neurodevelopment Fertilization Embryonic morphogenesis Induction of Neuroectoderm...
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Transcript of Outline of Neurodevelopment Fertilization Embryonic morphogenesis Induction of Neuroectoderm...
Outline of Neurodevelopment
Fertilization
Embryonic morphogenesis
Induction of Neuroectoderm
Neurulation
Differentiation:1. Formation and placement of neuroblasts2. Axonal outgrowth3. Growth cones, selective migration4. Selective fasciculation5. Target selection6. Synaptogenesis7. Etc…(cell shape, neurotransmitter, ionic channels, receptors)
Adult neuronal plasticity(Activity-dependent?)
Seg
men
tati
on
Selective Aggregation with DissociatedVertebrate and Invertebrate Tissues
suggest (Neuronal) Adhesion Molecules.
(Townes and Holtfretter, 1955)
1. Sponges (Wilson, 1907)
2. Amphibians (Townes and Holtfretter, 1955)
3. Chick (Moscona, 1952)
Epidermis+
Mesoderm
Do Molecular Cues Determine the Retinotectal Spatial-topic Map?
dorsal ventral
temporal nasalA(T)
P(N)
L(V)
M(D)
Retina
T N
D
V
Optic Tectum
M(D)
L(V)
A(T)
P(N)
D
V
T N
Retina
Subjective “up”
Optic Tectum
(T)
(N)
(D) (V)
Subjective “down”
(T)
(N)
(D) (V)
Retinotectal Map is Preserved DespiteExperimental Rotation of the Eye.
“Chemaffinity Hypothesis”(Sperry, 1956)
Rot
ate
Eye
180
o
N
V
D
T
Early Embryonic Insect Neurons form a Repeated Segmental Scaffold.
Identified neuronsCommissural
Tracts
LongitudinalTracts
Grasshopperembryo
Pioneer Neurons Create the Early Scaffold of the Adult Nervous System.
pioneer neuron
guidepost cells
growth cone
selectivefasciculation
Pioneer Neurons and Guidepost CellsGuide the Initial Path of Peripheral Nerve
Tracts in Embryonic Grasshopper Limb Buds.
PioneerNeurons
Guidepost Cells
(Bentley and Caudy, 1983)
Growth Cone
CT1 Photoablated Control
Growth Cones are Dynamic Sensory Organellesthat Guide the Growth of Embryonic Neurons.
Sensing and Transducing:• Diffusible Cues• Contact-dependent Cues• Trophic Factors• Neurotransmitters?
(Play GFP-Actin Growth Cone Movie)Andrew Matus, Friedrich Miescher Institute, Switzerland
(Play Time-Lapse Dendritic Spines Movie)Anna Dunaevsky and Rafael Yuste, Columbia U
Extracellular signal
Intracellular SignalingPathway
Ca+2
GTP
cAMP
CytoskeletalRearrangment
Identification of Molecules Mediating Axonal Guidance using Model Systems.
1. Biochemical approaches: Friedrich Bonhoeffer, retinotectal culture assay.
Temporal Nasal
Functional Assay
Fractionate Native Factors
ObserveNeuronal Specificity
Purify and IdentifyFactor
(Ephrins...)
Temporal Axons Nasal Axons
2. Molecular genetic approach: Corey Goodman, Drosophila screens for neurodevelopmental defects.
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 ofAxonal Guidance Molecules.
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.
IgGrepeats
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
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).
Human ROBO Mutation causes HGPPS(Horizontal Gaze Palsy with
Progressive Scoliosis)
HG
PP
SN
orm
al
(reduced hindbrain volume) (scoliosis)
(horizontal gaze palsy)
(Jen, et al., 2004)
Drosophila robo disruptsembryonic CNS scaffold
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