Lecture 7 - Developmental Neurobiology - Neurogenesis

What is neurogenesis?

how neurons are born from progenitor cells

What can cell fate be affected by?

Orienting plane of cell division

Do all progenitor cells become neurons?

Not all progenitors become neurons, some stay as progenitors next to the lumen in a region called the ventricular zone (VZ)

What is a radial glial cell?

A stem like cell whose nucleus/cell body is at the lumen, and has a long basal process

What are the 2 ways in which radial glia can divide?

1. Symmetrically

   • radial glial can divide to give more radial glia = production of 2 identical radial glia

     2. Asymmetrically

        • 1st daughter = identical as mother (radial glia) stays at lumen

        • 2nd daughter = acquires a neuronal identity - hops onto scaffold provided by its sister and moves outwards

Delta-Notch signalling, which is the receptor and signal?

• signal - Delta

• receptor - Notch (notch signalling pathway)

What is achaete scute proteins?

Transcriptional factor which when expressed at high levels will turn on TFs that tell a cell to become a neuron

What will a cell become if the notch signalling pathway is activated?

Support cell, remain as progenitor cells

What will a cell become if the notch signalling is not activated? (Notch signalling inhibited)

Neuron

What was notch pathway discovered in?

Drosophila (fly)

Wilt type mutants drosophila:

• clusters of cells in the neurogenic region that have activated proneural genes

• These cells are competent to become neuroblasts which delaminate and differentiate into neurons

Only a few do so

Proneural mutants

(no achaete scute)

• no cells become neural

• achaete scute needed to build up/to give neurons

• No achaete = no neurons

Neurogenic mutants

(No notch)

• more neurons are formed (lack of notch)

• if cell does not see notch = more neurons formed

CLINICAL WORK

1. Understanding of congenital conditions (through the understanding of signals and TFs that build the NS)

• Shh is expressed in floor plate-like cells in the forebrain and the spinal cord

• take away Shh - mice in which the Shh gene is knocked out (Shh -/-) (deleted) , the mice will develop but they will show holoprosencephaly and cyclopia

• Cyclopia = no floor plate = no eye fields separating into 2 = so 1 single eye

• Holoprosencephaly = occurs when the 2 sides of the brain don’t sit as separate sides but fuse into 1

CLINICAL WORK

2. Importance in drug discovery - disease understanding and regenerative medicine

• motor neuron disease

• through studies in mouse/chick/zebra fish

• —> we learned that neural plate is posteriorized through Wnt (+ retinoids acid signals) and its centralised through Shh

• apply BMP antagonists to mouse to get them to neural identity

• Apply Wnt + retinoic acid to get them to posterior identity

• Apply Shh to get them to ventral neural progenitors

What does Shh expression governs ventralisation along?

along the entire rosto-caudal axis

• due to intersection of Shh with factors that govern A-P regionalisation - different types of neurons are both at the same level along the A-P axis

What are the 3 types of neurons born at the same level along the A-P axis?

1. hypothalamic neurons

2. Midbrain DA neurons (degenerative in Parkinson’s disease)

3. Hindbrain serotonergic neurons ( poor function in depression)

Induced pluripotent stem cells (IPS cells)

• 2 step programme to support in vitro differentiation of human cells

  Step 1 - take a differentiated cell from the body and genetically re-programme it to a pluripotent stem cell fate

  Step 2 - culture IPS cells with the factors that control differentiation in the embryo - to get a dish of specialised cells

iPSCs - clinical application

• ability to differentiate

• vastly renewable

• easily accessible

• individual-specific (ie personalised/ non-immunogenic)

2015-current : generation of gastruloids

• 3D aggregates of embryonic stem cells that recapitulate the axial organisation of post-implantation embryos

• human gastruloids can be generated from human induced pluripotent stem cells

• Wnt inhibition can promote some aspects of brain development in gastruloids of some species but not in human

• gastruloids from some species can develop beating hearts