Upcoming Sessions April 22:Nervous System Development Lecture April 24:Reviews of Axonal Pathfinding in Sensory Systems April 29:Inner Ear Development Lecture May 1: Auditory System Pathfinding Research Papers May 6:Reviews of Organ of Corti Differentiation May 8:Hair Cell Differentiation Research Papers

Inner ear development Nervous 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)

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 ectoderm 3.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 and the 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 CSF 2.Neurons: generate and conduct electrical potentials 3.Glial cells: provide structure, insulate axons Numbers are staggering: o10 11 neurons associated with glia oEach neuron forms as many as 100,000 synapses with 1,000 to 1,000,000 other neurons oNeurons can be separated from their targets by distances of meters

Cell fate Neural vs. glial vs. epidermal fate is determined by the Notch-Delta pathway oInducing proteins are bound to the cell surface oCells 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 oCleaved 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 region 2.TARGET SELECTION: recognition of target cells and formation of connections 3.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