Neurodevelopment II Structure Formation. Reading: BCP Chapter 23

Transcription

1 Neurodevelopment II Structure Formation Reading: BCP Chapter 23

2 Phases of Development Ovum + Sperm = Zygote Cell division (multiplication) Neurogenesis Induction of the neural plate Neural proliferation Structure Formation Migration Aggregation Wiring the Brain Axon growth/synapse formation Neuron death/synapse refinement

3 Neural Migration Neural precursor stem cells are generated at the ventricular surface of the neural tube. As cells are generated, they begin moving to their addresses Time and location govern migration; numerous chemicals attract and repel cells Migrating cells are immature, lacking neurites (dendrites and axon) Ventricular surface There are two major ways for a cell to migrate: radial tangential

4 Methods of Migration Radial glial cells serve two functions: as progenitors to produce (by asymmetric cell division) neurons and glia; and as migratory guides for the newly generated neurons.

5 Migration Patterns Different migration patterns are observed in different parts of the nervous system. Spinal cord: radial PNS (neural crest cells); tangential Brain: radial (67%), tangential (33%) In cortex, excitatory neurons (pyramidal and spiny stellate cells) move via radial migration, whereas inhibitory neurons (GABAergic; aspinous stellate) move via tangential migration. Astrocytes also use radial migration, whereas oligodendrocytes use tangential.

6 Corticogenesis 1 Neocortex is composed of six layers. Neurons formed in the ventricular zone must migrate to their correct layer. In the process of corticogenesis, the preplate is created first. It separates into the marginal zone (future layer 1), where Cajal- Retzius cells release the protein Reelin, and the subplate below. Between these two plates, the cortical plate will develop from which the remaining five layers of cortex will develop.

7 Corticogenesis 2 Cortex is assembled inside-out. That is, the first cells to arrive in the cortical plate are those that will become layer VI cells. Next come layer V cells which migrate past those in layer VI, and so on. Reelin (released form the marginal zone) allows newly arriving cells to pass through existing plates. The subplate serves as a temporary terminal zone for thalamic inputs until layer IV is complete; at the end of corticogenesis, the subplate disappears.

8 Corticogenesis 3 Cell differentiation (cell fate) is the result of specific spatiotemporal patterns of gene expression. Neuro-progenitor cells (NPCs) initially express high levels of pro-neural genes (e.g., neurogenins). Later, this level drops and NPCs become gliogenic. Neurogenic cells migrate to the cortical plate where they differentiate into the various neuronal subtypes based on the levels of many transcription factors (e.g., BMP, SHH, NeuroD1, Sox5, Fezf2). Gliogenic cells differentiate first into astrocytes then later into oligodendrocytes as Notch signaling decreases from high to low.

9 Corticogenesis 4 Connections "up" and "down" within the thickness of the cortex are much denser than connections that spread from side to side. This columnar organization is reflected in the characteristic polarity of pyramidal cell neurites. Pyramidal cells have a large apical dendrite that extends upwards towards layer I (and the pia) and an axon that projects in the opposite direction. The protein semaphorin 3A, secreted by cells in the marginal zone, attracts dendrites and repels axons. high Sem3A concentration low

10 Spinal Cord Development 1 The spinal cord comprises two different areas: an inner H- shaped core of gray matter (cell bodies) and an outer area of white matter (myelinated axons). Neural stem cells (radial glial cells) proliferate and differentiate into precursor cells around the central canal. Migration of precursor stem cells is predominantly radial in nature. However, the cells do not migrate to the edge of the tube. inner mantel zone: grey matter outer marginal zone: white matter radial glial cells (future radial glial cells) Pia mater

11 Spinal Cord Development 2 Cell fate decisions in the spinal cord are controlled primarily by three morphogens. Release of BMP and Wnt from the roof plate causes dorsally-located neural precursor cells to develop into sensory neurons. On the other hand, release of SHH from the floor plate induces ventrally-located precursor stem cells to become motor neurons.

12 PNS Development 1 The peripheral nervous system (PNS) consists of the nerves and ganglia outside of the brain and spinal cord. Its main function is to connect the CNS to the external (somatic) and internal (autonomic) environments. The PNS develops from neural crest cells; migration of precursor stem cells is tangential in nature.

13 PNS Development 2 Neural crest stem cells can differentiate into many different cell and tissue types, thus cell fate decisions in the PNS are controlled by complex spatiotemporal patterns of gene expression. BMP, Wnt and Notch have each been identified as key signaling regulators of neural crest cell differentiation. Notch Wnt BMP

14 Aggregation 1 After migration, cells align themselves with others cells and form structures. Aids to aggregation: Cell-Adhesion Molecules (CAMs) Gap junctions pass cytoplasm between cells Morphogenic factors Cell adhesion Gap junctions Biological Science 2005

15 Aggregation 2 The commissural plate is located at the anterior pole of the developing neural tube. It is thus in a position to act as a center for rostral-caudal patterning in cortex. Cells in this area release the morphogen fibroblast growth factor (Fgf8). In turn, Fgf8 affects the expression level of the transcription factors Pax6 and Emx2. Fgf8 (and Pax6) promote the development (size/position) of anterior structures, while Emx2 promotes the development of posterior structures.

16 Aggregation 3 If mice are genetically engineered to produce less Emx2, then there is an expansion of anterior cortical areas, such as motor cortex (M) and a shrinkage of posterior cortical areas such as visual cortex (V). Conversely, if Pax6 is knocked out, then there is an expansion of visual cortex and a shrinkage of motor cortex.