development of the nervous system
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Development of the Nervous System. Feb., 2014 Hugo J. Bellen Baylor College of Medicine/HHMI. Human Nervous System. The ‘ Seven Questions ’ of Neuronal Development. Neuronal Induction Neuronal Differentiation Neuronal Migration Axon Pathfinding Target Recognition Synapse Formation - PowerPoint PPT PresentationTRANSCRIPT
Development of the Nervous SystemDevelopment of the Nervous System
Feb., 2014Feb., 2014
Hugo J. BellenHugo J. Bellen
Baylor College of Medicine/HHMIBaylor College of Medicine/HHMI
Human Nervous SystemHuman Nervous System
1.1. Neuronal InductionNeuronal Induction2.2. Neuronal DifferentiationNeuronal Differentiation3.3. Neuronal MigrationNeuronal Migration4.4. Axon PathfindingAxon Pathfinding5.5. Target RecognitionTarget Recognition6.6. Synapse FormationSynapse Formation7.7. Synapse EliminationSynapse Elimination
Etc….Synapse Maintenance/Aging/PlasticityEtc….Synapse Maintenance/Aging/Plasticity
The ‘Seven Questions’ of Neuronal DevelopmentThe ‘Seven Questions’ of Neuronal Development
Forward genetics can be done in model Forward genetics can be done in model organisms like worms and fliesorganisms like worms and flies
Identification of the genes then tells us Identification of the genes then tells us something about the molecular mechanismssomething about the molecular mechanisms
Identifying genes that cause developmental defects is at the core of the success of studying
nervous sytem development
Identifying genes that cause developmental defects is at the core of the success of studying
nervous sytem development
Genes encode the information for proteins, which are the building blocks of organisms
Genes are evolutionarily conserved: striking parallels between flies and humans amazing similarities between mice and humans
Once a system developed in an ancestral species, the building blocks (= proteins encoded by genes) are almost always maintained during evolution: e.g. muscle, nervous system)
Genes encode the information for proteins, which are the building blocks of organisms
Genes are evolutionarily conserved: striking parallels between flies and humans amazing similarities between mice and humans
Once a system developed in an ancestral species, the building blocks (= proteins encoded by genes) are almost always maintained during evolution: e.g. muscle, nervous system)
Why is information gained from animals relevant to human biology?
Why is information gained from animals relevant to human biology?
Is much higher than previously thought
Has been confirmed in numerous ways including sequencing
Can be extremely informative to study and analyze biological processes across organisms
The basis for much of the success of biology in unraveling the mechanisms by which disease occur in the past 30 years
Is much higher than previously thought
Has been confirmed in numerous ways including sequencing
Can be extremely informative to study and analyze biological processes across organisms
The basis for much of the success of biology in unraveling the mechanisms by which disease occur in the past 30 years
Evolutionary ConservationEvolutionary Conservation
from Volker Hartenstein
Sensory organs of an adult DrosophilaSensory organs of an adult Drosophila
In each segment there are 60 neuroblasts, 30 on each side
They produce about 350 cells per hemisegment
Cell lineage is invariant for each neuroblast: this fate is acquired via positional information from the neurectoderm
The cartesian grid-like expression pattern repeats itself in each segment specifying the same sets of neuroblasts
The VNC as a modelThe VNC as a model
Patterning and specification of NBs
• Patterns of proneural clusters and NB are identical.• Interaction of AP/DV gene activities specifies NB fates
Sight: eyesSight: eyes
Smell: olfactory receptors in antenna (nose)Smell: olfactory receptors in antenna (nose)
Taste: taste receptors in labia and legs (tongue)Taste: taste receptors in labia and legs (tongue)
Hearing: Johnston organ in antenna (ear)Hearing: Johnston organ in antenna (ear)
Proprioception: external sensory organs spread Proprioception: external sensory organs spread over body (skin)over body (skin)
Peripheral senses in fliesPeripheral senses in flies
External sensory organs :a model to unravel the development of the PNS
External sensory organs :a model to unravel the development of the PNS
Asymmetric division
Lateral inhibition
Proneural proteins and Notch signaling during sensory bristles development
Proneural proteins and Notch signaling during sensory bristles development
Loss of Notch
wild-type
Lateral inhibition Asymmetric division
Loss of Notch signaling results in aberrant bristle development
Loss of Notch signaling results in aberrant bristle development
pI
IIa IIb
st nso sh
pI
IIb
n n
pI
IIa
so so
IIb
n n
IIa
so so
wild-typewild-type gain of gain of NotchNotchloss of loss of NotchNotch
Sensory lineage in WT and Notch mutationsSensory lineage in WT and Notch mutations
Cell fate decision: nervous system, blood, Cell fate decision: nervous system, blood, vasculature, pancreasvasculature, pancreas
Asymmetric divisions: neurogenesis, Asymmetric divisions: neurogenesis, myogenesismyogenesis
Maintenance of undifferentiated state: Maintenance of undifferentiated state: hematopoietic, muscle and neural stem cellshematopoietic, muscle and neural stem cells
Differentiation: skin, oligodendrocytes, boneDifferentiation: skin, oligodendrocytes, bone
Notch signaling regulates multiple processes during animal development in vertebrates
Notch signaling regulates multiple processes during animal development in vertebrates
Butler, S. J. et al. Development 2007;134:439-448
General mechanisms of axon guidanceGeneral mechanisms of axon guidance
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Science 274, 1123 (96)
Slit pathway:Slit, Robo, commissureless
Slit pathway:Slit, Robo, commissureless
29
Keleman et al. (2002) Cell 110, 415
Model for Comm function
(A and B) comm is the switch that controls midline crossing. In an ipsilateral neuron, comm is OFF. The
growth cone carries high levels of Robo and is repelled by Slit. In a commissural neuron, comm is initially ON. Once the
commissural growth cone reaches the other side, comm is turned OFF in order to increase Robo levels and prevent
recrossing (B).
(C) Comm regulates Robo trafficking. If comm is OFF, Robo is packaged into vesicles delivered to the growth cone. If comm is ON, most Robo is sorted by Comm into vesicles
bound for late endosomes and lysosomes. Vesicles travelling to the growth cone thus contain very little Robo, and allows it
to extend across the midline.
LPSY motif is the Comm’sendosomal sorting signal.
Myat et al. (2002). Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor. Neuron 35, 447-59.
Keleman et al. (2005) Nature Neurosci. No evidence for Nedd4 function in midline crossing