Upcoming Sessions

April 22: Nervous System Development Lecture

April 24: Reviews of Axonal Pathfinding in Sensory Systems

April 29: Inner Ear Development LectureMay 1: Auditory System Pathfinding

Research PapersMay 6: Reviews of Organ of Corti

DifferentiationMay 8: Hair Cell Differentiation Research

Papers

Inner ear developmentNervous system development

Nervous System Development

• Formation and differentiation of the neural tube

• Tissue architecture of the central nervous system

• Differentiation of neurons/generation of neural diversity

• Pattern generation in the nervous system

Chick Embryo Whole Mounts

Primary Neurulation(formation of neural tube)

MHP=medial hinge point

Neural groove

Primary Neurulation (cont’d)

Primary Neurulation (cont’d)3 steps:

1. Formation of the neural plate• Underlying dorsal mesoderm signals ectodermal cells

to elongate and form the neural plate (columnar cells)2. Bending of the neural plate

• MHP cells become anchored to the notochord and change shape forcing formation of the neural groove

• DLHP cells become anchored to the surface ectoderm3. Closure of the neural tube

• Folds adhere to each other and cells merge• In mammals, cranial neural crest cells migrate to the

folds; spinal NC cells don’t migrate until after closure• Neural tube don’t close simultaneously (3 sites in

mammals): anterior neuropore closes first• Separation from surface ectoderm occurs when neural

tube cells switch from expressing E-cadherin (like ectoderm) to N-cadherin and N-CAM

Secondary Neurulation

• Mesenchyme cells coalesce into a solid cord that subsequently forms cavities that combine to form the hollow tube

• Separately formed tubes join together

• Occurs at transition regions at the junctions of tubes formed via primary neurulation

Nervous System Development

• Formation and differentiation of the neural tube

• Tissue architecture of the central nervous system

• Differentiation of neurons/generation of neural diversity

• Pattern generation in the nervous system

Human Brain Development

Neural Stem Cells andthe Location of Dividing Cells

Cell Migration

After their terminal division, cells migrate from the lumen toward the surface

Lamination

Cells with the earliest birthdays migrate the shortest distances

Adult Stem Cells

Nervous System Development

• Formation and differentiation of the neural tube

• Tissue architecture of the central nervous system

• Differentiation of neurons/generation of neural diversity

• Pattern generation in the nervous system

Generation of neurons

• Neural stem cells can become:1. Ventricular (ependymal) cells: make CSF2. Neurons: generate and conduct electrical

potentials3. Glial cells: provide structure, insulate axons

• Numbers are staggering:o 1011 neurons associated with 1012 gliao Each neuron forms as many as 100,000

synapses with 1,000 to 1,000,000 other neurons

o Neurons can be separated from their targets by distances of meters

Cell fate

• Neural vs. glial vs. epidermal fate is determined by the Notch-Delta pathwayo Inducing proteins are bound to the cell surfaceo Cells expressing Delta, Jagged or Serrate

proteins activate adjacent cells that express the Notch protein by causing a conformational change that causes Presinilin-1 to cleave part of the Notch intracellular domain

o Cleaved portion of Notch goes to the nucleus and activates transcription factors

Neuronal type

• Determined initially by dorsal/ventral position within the neural tube, which is established by birthdate

• Gradients of paracrine factors then cause differential gene expression which determines type (e.g., motor vs. sensory)

• Early-born neurons can secrete retinoid signals that alter gene expression of later-born neurons as they migrate through to their final position

Dorsal/ventral Specification

• Eventually, in spinal cord dorsal=sensory ventral=motor

• Ventral is specified by notocord, via Sonic hedgehog (Shh) converts MHC to become floor plate more Shh

• Dorsal by ectoderm via TGF-β roof plate more TGF-β

Paracrine Factor Gradients

Motor neurons(PNkx6.1 and Pax6 overlap)

Neurites

Growth Factors

Nervous System Development

• Formation and differentiation of the neural tube

• Tissue architecture of the central nervous system

• Differentiation of neurons/generation of neural diversity

• Pattern generation in the nervous system

Specificity of Axonal Connections

3 steps:1. PATHWAY SELECTION: route to a specific

region2. TARGET SELECTION: recognition of target

cells and formation of connections3. ADDRESS SELECTION: refinement of

synapses so that each axon contects to a small subset of its initial connections

• First 2 steps are independent of activity; final step often requires synchronized electrical potentials

Pathway Selection

• Extracellular matrix proteins and growth factors provide navigation cues to growth cones

ECM(laminin vs. collagen)

Signalling molecules(ephrins, semaphorin, netrin and Split)

Target selection

• Growth factors released from target tissues act over very short distances to either attract or repel axons during their final approach to the target

Address Selection(activity dependent

refinement)• Competition between axons for

innervation less active synapses are eliminated

Neuronal cell death

• Target tissue regulates the number of axons innervating it via neurotrophic factor concentration

• Neurons that lose their target innervation die

Visual System Development

Central Auditory System Pathways