Development of the Nervous System Feb., 2014 Hugo J. Bellen Baylor College of Medicine/HHMI

Human Nervous System

1. Neuronal Induction 2. Neuronal Differentiation 3. Neuronal Migration 4. Axon Pathfinding 5. Target Recognition 6. Synapse Formation 7. Synapse Elimination Etc….Synapse Maintenance/Aging/Plasticity The ‘Seven Questions’ of Neuronal Development

Forward genetics can be done in model organisms like worms and flies Identification of the genes then tells us something about the molecular mechanisms 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?

 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 Conservation

from Volker Hartenstein Sensory 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 model

Patterning and specification of NBs Patterns of proneural clusters and NB are identical. Interaction of AP/DV gene activities specifies NB fates

 Sight: eyes  Smell: olfactory receptors in antenna (nose)  Taste: taste receptors in labia and legs (tongue)  Hearing: Johnston organ in antenna (ear)  Proprioception: external sensory organs spread over body (skin) Peripheral 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

Loss of Notch wild-type Lateral inhibition Asymmetric division Loss of Notch signaling results in aberrant bristle development

pI IIaIIb stnsosh pI IIb nn pIIIa so IIb nn IIa so wild-type gain of Notch loss of Notch Sensory lineage in WT and Notch mutations

 Cell fate decision: nervous system, blood, vasculature, pancreas  Asymmetric divisions: neurogenesis, myogenesis  Maintenance of undifferentiated state: hematopoietic, muscle and neural stem cells  Differentiation: skin, oligodendrocytes, bone Notch signaling regulates multiple processes during animal development in vertebrates

Butler, S. J. et al. Development 2007;134: General mechanisms of axon guidance

27 Science 274, 1123 (96)

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’s endosomal 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, Keleman et al. (2005) Nature Neurosci. No evidence for Nedd4 function in midline crossing