Brain Development & Neurogenesis

Fertilisation to Gastrulation

• Fertilisation → embryo formation → cell division → blastocyst

• Cells accumulation in one corner forming inner cell mass

• Gastrulation then occurs where the one layer forms the 3 germ layers (ecto, meso and endoderm)

Endoderm, Mesoderm & Ectoderm

Endoderm	Mesoderm	Ectoderm
Inner Forms digestive tract, lungs, liver and pancreas	Middle Muscles, skeleton kidneys and sex organs	External Skin & neurons

Neurolation

• After gastrulation

• Lateral folds of the neural plate (in the ectoderm) roll up and fuse to form the neural tube.

• Neural plate formed → invagination forms neural groove → neural groove buds off → neural tube is formed

• Tube subdivides into sections e.g. prosencephalon becomes cerebral hemispheres

  

Signalling Factors

• Neuroepithelium progressively subdivides into distinct regions based on instructions from small groups of cells called organisers

• Organisers release signaling factors that control the actions and movements of neighbouring cells - controls their identity.

  • Bone morphogenic proteins

  • Fibroblast growth factors

  • Wnts

  • Sonic hedgehog (top of neural tube)

• During development these signalling factors establish a gradient to provide positional information

• Establish a crude initial pattern

Formation of Neurons

• Neuroepithelial cells divide

• As brain epithelium thickens they elongate and differentiate into cells known as radial glial cells

• Radial glial cells divide asymmetrically to generate neurons (directly and indirectly) during the neurogenic period

• Radial glial cells are also used as a ladder for immature neurons to climb up to the cortical plate using cell adhesion mechanisms

• Radial glial cells will convert into glial

  

Neural differentiation

• Signaling molecules induce the expression of specific genes, resulting in specific cell types

• bHLH = basic helix loop helix

  • Can cross regulate

  • Depends on context

  • Cell fate and self-renewal of NPCs is regulated by bHLH transcription factors.

  • NPC maintenance = Hes and Id

• HESS can control neural differentiation and promote maintenance of these precursor cells

• Pro-Neuronal = Neurog1/2, Ascl1.

• In the absence of neuronal precursors they become astrocytes

• Oleg1/2 cause differentiation into oligodendrocytes (occurs once all the neurons are in correct positions and have supportive glia)

Corticogenesis

• Division and neurogenesis.

• Migration from ventricular zone to the cortical plate

• Neuritogenesis extension of axons and dendrites

• Synaptogenesis formation of synapses

• If one of these doesn’t form properly cortical malformations will occur and manifest as macroscopic anatomical defects that are visible with brain imaging techniques (MRI)

How does cortical folding occur?

• Radial glial cells

• In regions destined to become gyri (protogyri) have greater densities of progenitor cells than regions destined to become sulci (protosulci)

• Differences in these progenitor cells result in different production and accumulation of neurons in the developing cortical plate

• Progressive differences in the trajectories of the radial glial cells fibres during gyri (fan) and sulci (parallel to limit the spread of migrating neurons) formation

• Sonic hedgehog stimulation results in an increased density of glial cells - inhibition leads to smaller gyri

Neural Migration During Neurogenesis

• Tangential neuronal migration (usually inhibitory GABA): Move parallel to ventricular surface (when neurons need to migrate to the cerebral wall)

• Positions are established using radial or tangential migration

• Allow different types of neuron cells to populate different regions of the brain

• Radial migrating neurons are usually excitatory (glutamate)

• Glutamate neurons develop in the dorsal forebrain

• GABA neurons develop from the ventral forebrain (move forward via tangential migration)

  

Establishing Polarity

• After neurons are born they must break symmetry and establish the axon and dendrites

• Neurons extend multiple minor nurites, making them multipolar.

• The multipolar cell generates a trailing process (axon) and a leading process (dendrite) - now bipolar

• Bipolar cells migrate towards the cortical plate along radial glial cells - when the minor nurite makes contact this becomes the leading process

• Regulated by adherin which controls dendrites specification

• When a minor nurite of a multipolar cell touch a pineering axon it becomes an axon due to TAG1

  

Maintaining Polarity

• Must maintain different proteins in axons and dendrites as they have different ion channels, cytosolic element, and cytoskeletal elements.

• Selective sorting, transportation and delivery of proteins helps maintain neuronal polarity

  • This is via different vesicles that are either dendritic or axonal

  • Axonal is biased towards axons but can go to dendrites

  • Dendritic can only go to dendrites

• Cargo (signal sequence) + adaptor (signal recognition) = correct sorting.