N371: Neurodevelopment + CNS patterning

Is development a reversible process?

No, cells lose potency as they specialize (one-way process).

What are induced pluripotent stem cells (iPSCs)?

Specialized cells reprogrammed back to a stem-like state using specific factors.

What is an assembloid?

A fusion of two or more brain organoids representing different regions.

Why are assembloids useful?

Why are assembloids useful?

What controls neural development at the molecular level?

Gene regulatory networks.

How do gene regulatory networks work?

Environmental cues → activate transcription factors → change gene expression → determine cell fate.

What defines a “cell type”?

A group of transcriptionally similar cells.

What is cell proliferation?

Making more cells through division.

What is cell differentiation?

Cells becoming specialized in structure and function.

What is morphogenesis?

Cells and tissues shaping into structures and organs.

What is programmed cell death (apoptosis)?

Controlled removal of unnecessary cells (e.g., separating fingers, refining brain wiring).

What happens during gastrulation?

The inner cell mass of the blastocyst forms three germ layers.

What are the three germ layers?

Endoderm, mesoderm, and ectoderm.

What does the endoderm form?

Internal organs.

What does the mesoderm form?

Muscles and bones.

What does the ectoderm form?

The nervous system (and skin).

How do cells “know” what to become during gastrulation?

By cues from their environment and neighboring cells.

What is neurulation?

Formation of the neural tube from the ectoderm

What is the notochord, and what is its function?

A transient mesodermal structure that signals overlying ectoderm to form neuroectoderm.

What does the ectoderm directly above the notochord become?

The neural plate.

What do cells at the edges of the neural plate become?

Neural crest cells.

What does ectoderm farther from the notochord become?

Surface ectoderm (skin).

What are neural folds?

The raised lateral edges of the neural plate.

What forms when the neural folds fuse?

The neural tube.

What is the neural groove?

The midline depression between neural folds before fusion.

What does the neural tube develop into?

The central nervous system (brain + spinal cord).

What do neural crest cells give rise to?

Much of the peripheral nervous system and other important cell types.

What is the anterior (cranial/rostral) neuropore? What happens if the anterior neuropore fails to close?

The opening that becomes the brain; closes first. Anencephaly

What is the posterior (caudal) neuropore? What happens if the posterior neuropore fails to close?

The opening that becomes the spinal cord. Spina bifida.

What is paracrine signaling?

Local communication — a cell releases ligands that diffuse a short distance to nearby cells.

What is juxtacrine signaling?

Direct communication — a ligand on one cell binds to a receptor on an adjacent cell.

What is dorsoventral patterning?

Organization of the developing nervous system along its top-to-bottom (dorsal-ventral) axis.

How does dorsoventral patterning occur?

Through paracrine signaling that exposes cells to different concentrations of morphogens.

What does the roof plate (dorsal) release, and what does it form? (Dorsoventral patterning)

Releases BMPs → forms sensory neurons and dorsal interneurons.

What does the floor plate (ventral) release, and what does it form? Dorsoventral patterning)

Releases SHH (sonic hedgehog) → forms motor neurons and motor interneurons.

What is anteroposterior patterning?

Organization of the developing nervous system along the head-to-tail axis.

What brain regions are arranged by anteroposterior patterning?

Forebrain → midbrain → hindbrain → spinal cord.

How do neurons migrate during cortical development? What do they migrate along?

In an inside-out fashion — from ventricular zone outward to cortex. Migrate along long radial glia fibers.

What is symmetric progenitor division?

1 radial glia → 2 identical radial glia (stays in ventricular zone).
Purpose: Expands progenitor pool for larger cortex later

What is asymmetric neurogenesis (Radial Unit Hypothesis)?

1 radial glia (stays) → 1 neuron (migrates out).
Purpose: Makes neurons while keeping progenitors; builds cortical columns.

What is symmetric neurogenic expansion (Immediate Progenitor Hypothesis)?

1 radial glia → 2 intermediate progenitors (IPCs), which each divide into neurons.
Purpose: Rapidly boosts neuron numbers — one radial glia can yield up to 4 neurons.

What is cortical expansion?

Growth in cortical surface area due to progenitor proliferation, neuron formation, and synapse development.

In what order do cortical layers form?

Inside-out — layer 6 first, then 5, then 4, etc.

Where is the ventricular zone (VZ) located?

Right next to the brain’s ventricles — the innermost germinal layer.

What type of cells live in the ventricular zone?

Radial glia — the primary neural stem cells.

What are the main functions of the ventricular zone?

Self-renewal of progenitors and production of neurons or intermediate progenitor cells (IPCs).

Is the ventricular zone present in all vertebrates?

Yes, it’s conserved across all species.

Where is the inner subventricular zone (ISVZ)?

Just above the ventricular zone.

What cells are found in the ISVZ?

Intermediate progenitor cells (IPCs) and inner radial glia.

What is the function of the ISVZ?

IPCs divide one or two more times to generate neurons.

What’s the main purpose of the ISVZ?

Boosts neuron production beyond what the VZ alone can do.

Where is the outer subventricular zone (OSVZ)?

Farther from the ventricles, above the ISVZ.

What type of cells dominate the OSVZ?

Outer radial glia (oRG) — specialized stem cells.

What’s special about outer radial glia?

They lack ventricular contact but can still self-renew and make neurons.

Why is the OSVZ important in evolution?

It supports massive cortical expansion and folding — key to primate brain growth.

Which species have a prominent OSVZ?

Primates (including humans).

What’s the main difference between VZ and OSVZ radial glia?

VZ cells touch the ventricle (apical contact); OSVZ cells don’t but still divide and produce neurons.

What is the function of radial glia progenitors?

They self-renew or produce neurons — the “factories” of the cortex.

What are transient circuits?

Temporary circuits that exist only during development and later undergo apoptosis.

What is the subplate?

A transient layer below the cortical plate containing early-born neurons.

What are the main roles of the subplate?

Guides neuron placement, early wiring, thalamic inputs, and plasticity.

How can you think of the subplate metaphorically?

Like a “lobby” — neurons waiting before entering the main building (cortex). 🙂

What is the cortical plate?

The layer above the subplate that becomes the permanent six-layered cortex.

What’s the big picture role of the subplate and cortical plate?

Together they enable cortical expansion and folding — foundation of complex human brains. Above the VZ/ISVZ/OSVZ

What type of signaling is Notch–Delta?

Juxtacrine signaling (cell-to-cell contact).

What is the function of Notch–Delta signaling in brain development?

Prevents all progenitors from differentiating into neurons at once — maintains balance.

In Notch–Delta signaling, which molecule is the receptor, and which is the signal?

Notch = receptor, Delta = signal.

What happens to the cell with more Delta?

It becomes a neuron.

What happens to the cell with more Notch?

It stays a progenitor (due to lateral inhibition).

How does Notch-Delta signalling work?

Delta on one cell binds to Notch on a neighboring cell → Notch is cleaved → NICD fragment enters the nucleus → turns on genes that inhibit neuronal differentiation → that cell stays a progenitor, while the Delta-high cell becomes a neuron.

What are the two main neuron classes in the cortex?

Projection neurons and interneurons.

What is the function of projection neurons?

Excitatory (glutamatergic), send long-distance signals to other brain regions.

Where are projection neurons born?

In the ventricular and subventricular zones (VZ + SVZ) of the dorsal telencephalon.

How do projection neurons migrate?

Radially along radial glia — perpendicular to the cortical surface.

What is the function of interneurons?

Inhibitory (mostly GABAergic), local processing — balance excitation with inhibition in circuits.

Where are interneurons born?

In the ventral telencephalon — the medial and lateral ganglionic eminences (MGE, LGE).

How do interneurons migrate?

Tangentially — parallel to the cortical surface before integrating into cortex.

How can scientists model human brain development in vitro?

By growing embryoid bodies from stem cells that self-organize into brain organoids.

What is an organoid?

A mini 3D tissue containing many brain cell types but not a full brain.

What are tonotopic maps?

Ordered brain maps representing sound frequencies.

How is frequency represented in the cochlea?

• Base (stiff, narrow) → high frequencies.

• Apex (flexible, wide) → low frequencies.

What is retinotopic mapping?

The spatial layout of the retina is preserved in the visual cortex (V1). Allows visual information to be organized like a “pixel-by-pixel” image.

What is axon guidance?

The process by which axons navigate toward their correct targets through a series of directional decisions.

What are guidance cues?

Molecular signals that direct axon growth during development. Detected by lamellipodia and filopodia 

How do growth cones respond to guidance cues?

By detecting molecular gradients and turning or changing growth rate to move up or down the gradient.

What happens with attractive signals?

Growth cones turn toward the signal.

What happens with repulsive signals?

Growth cones turn away from the signal.

What is activity-dependent circuit formation?

The process by which electrical activity refines synaptic connections to create functional neural networks.

What is Hebb’s rule?

“Neurons that fire together, wire together; neurons that fire out of sync lose their link.”

What is the relationship between guidance cues and activity?

Guidance cues = the blueprint (rough map); activity = fine-tuning (refines and prunes connections).

What is the role of activity in map refinement?

Combines molecular cues and neural firing patterns to achieve precise wiring.

What are retinal waves?

Spontaneous waves of action potentials across neighboring retinal ganglion cells (RGCs). Signal to brain that those RGCs represent nearby points in visual space — their axons should stay close together.

What happens if retinal waves are absent?

Retinotopic maps become fuzzy and disorganized.

What happens to synchronous inputs onto a neuron?

Synapses are strengthened and branch additions decrease (stabilized, precise connections).

What happens to asynchronous inputs?

How do axons change over time during development?

They start branchy and exploratory, then become refined and stable as synchronous activity strengthens correct connections.

What is the path of neuronal migration during cortical development?

VZ → ISVZ → OSVZ → subplate → cortical plate