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