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BCP Chapter 23

Neurodevelopment I Neurogenesis

Neural development is an ongoing,

complex process involving

interactions between genes and the

environment. There can be dire

consequences when something goes

wrong.

Genetic and environmental causes of

nervous system disorders include: • gene copy number variation

• mutations in genes (single nucleotide

polymorphisms) or regulation regions

toxins, viruses (e.g., Zika), stress

Neurodevelopmental disorders: autism; schizophrenia, Down syndrome,

fragile X, ADHD, dyslexia, verbal dyspraxia

Psychiatric Disorders: anxiety, affective

Neurodevelopment

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

Germinal Stage

The germinal stage of embryo-

genesis, refers to the time from

fertilization to implantation in the

uterus. The germinal stage takes

around 8-10 days.

Potency: the ability to develop

into different cell types • totipotent: fertilized egg morula

• pluripotent (embryonic stem cells):

blastocyst

• multipotent; unipotent

At the end of the germinal stage,

there is a “Baby in a Compact

Disc”.

morula

Gastrulation

Neurulation

The third phase of development is neurulation, the stage at which the nervous

system emerges. The mammalian nervous system is derived from the ectoderm

– the outermost germ layer – of the embryo. In the third week of human

development, a neural plate forms along the dorsal side of the embryo. The

edges of this plate elevate and meet at the mid-line forming a neural tube. This

tube is the precursor of the central nervous system.

Neurulation stage

• Neural tube: CNS

• Inside tube: ventricles

and spinal canal

• Neural crest: PNS

• Somite: skull and

vertebrae

thebrain.mcgill.ca

A central question in developmental

biology is how form and pattern emerge

from the simple beginnings of a

fertilized egg. Are cell fates somehow

predetermined or do cells and tissues

interact with one another to orchestrate

developmental processes (induction)?

Embryonic induction was first shown

unambiguously by the results of

experiments conducted by Mangold and

Spemann (1924), wherein the

transplanted dorsal lip of one frog

blastopore induced a second neural

tube in a recipient frog embryo.

The dorsal lip – future mesoderm (the

notochord in humans) – is known as the

organizer.

Induction 1

Induction of the neural plate is caused not

by an excitatory signal from the mesoderm

but by blockade of an inhibitory one within

the ectoderm itself (a process called

disinhibition).

Prior to gastrulation, cultured regions of

ectoderm develop into epidermis. However,

if the cells are dissociated – separated by

removal of calcium from the medium – then

the cells become neurons. This suggests

that neural fate is actively suppressed by

cellular associations in ectoderm.

If bone morphogenetic protein (BMP) is

added to the dissociated culture dish, then

the cells again develop into epidermis.

Thus, BMP inhibits (prevents) a neural fate.

Induction 2

The current model of neural

induction is that the dorsal lip in

amphibians (notochord in

humans) releases several

molecules that interfere with the

BMP signals between overlying

ectodermal cells.

Ceberus (Cb), chordin (Chd),

noggin (Nd) and follistatin all

interfere with the activation of the

BMP receptor in ectoderm,

thereby blocking its anti-neural

effects. Thus, these chemical

signals “induce” this region of the

embryo to develop into neural

tissue ultimately generating the

brain and spinal cord.

Induction 3

Neural Tube

Following neurulation, the neural

tube forms two plates. • In response to BMP released by the

overlying non-neural ectoderm, the

dorsal aspect of the tube develops into

a tissue known as the roof plate. It

then begins to release BMP (and Wnt).

• In response to the release of sonic

hedgehog (SHH) from the underlying

notochord, the ventral part of the tube

becomes flattens into the floor plate. It

then begins to secrete SHH.

The cells between the two plates will

proliferate and differentiate into the

neurons in the brain and spinal cord.

Neural Proliferation 1

Neural Proliferation 2

Neural stem cell proliferation

(symmetric cell division) and

differentiation (asymmetric cell

division) is controlled by multiple

factors: • morphogenetic factors

• cell-to-cell signaling

Morphogens are soluble molecules

that diffuse and control cell fate

decisions in a concentration-

dependent fashion. • dorsal plate: BMP, Wnt

• ventral plate: SHH

In direct cell-to-cell signaling,

neighboring cells influence one

another. If one cell differentiates,

then it suppresses differentiation in

others via Notch (lateral inhibition).

BMP

Wnt

SHH

Neural Proliferation 3

Proliferation and differentiation

cause the neural tube to change

its size and shape (morphology).

Shape changes are quite

pronounced at the rostral end of

the tube (future brain and

cerebellum), whereas they are

minor at the caudal end (future

spinal cord).

In temporal order, the rostral end

of the tube shows:

• first, three swellings which will

give rise to the forebrain,

midbrain and hindbrain

• second, five swellings which

give rise to major divisions of

the brain.

Gross Morphology

Milestones in the morphological

development of the forebrain

include: • flexion forward (in humans)

• posterior growth of the

telencephalic swellings such that

they lie over, lateral to and fuse

with the diencephalon

• sprouting from the diencephalon

of optic stalks and cups that give

rise to the optic nerves and

retinas (for vision)

• sprouting from the ventral surface

of the cerebral hemispheres of

the olfactory bulbs (smell)

Telencephalon surrounds the

lateral ventricles; diencephalon

is on either side of the third

ventricle.

Forebrain

Lateral

ventricles

Third

ventricle

Telencephalon

Diencephalon

Milestones in the morphological

development of the midbrain

include: • the dorsal surface (tectum) shows

four bumps (colliculi)

• the floor of the midbrain becomes

the tegmentum, and projection

fibers accumulate on the lateral

edges (cerebral peduncles;

pyramidal motor tracts)

• the cerebral aqueduct narrows

Mesencephalon surrounds the

cerebral aqueduct.

Midbrain

Cerebral

peduncles

Milestones in the morphological

development of the hindbrain

include: • in metencephalon (the rostral

hindbrain), tissue along the

dorsal-lateral wall grows to form

the rhombic lips, which then

expand further dorsally until they

fuse forming the cerebellum

• in myelencephalon (the caudal

hindbrain), the ventral and lateral

walls swell such that the fourth

ventricle is at the roof, and

projection fibers (the pyramids)

pass along the ventral surface

Metencephalon surrounds the

fourth ventricle; myelencephalon

is below the fourth venticle.

Hindbrain

The mature brain continues to change

and adapt

Experience can reorganize the

adult cortex (learning and memory)

Neurogenesis (growth of new

neurons) is seen in the olfactory bulb

and hippocampus

Neuroplasticity in Adults