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• Neural tissue forms from a subset of ectodermal cells in the developing embryo.
• Cell identity is specified along the anterior-posterior and dorsal-ventral axes.
• Specific neural cell types are defined during early neural development.

Embryonic Germ Layers

• Gastrulation, a rearrangement of cells in the early embryo, leads to the formation of three distinct layers.
• The ectoderm gives rise to neural tissue and skin and is the outermost layer. The entire nervous system originates from the ectoderm.
• The mesoderm, the middle layer, becomes the skeleton, muscle, kidney, heart, and blood.
• The endoderm, the innermost layer, forms the gut, liver, and lungs.

Neural Lineages and Gastrulation

• During gastrulation, the dorsal or axial mesoderm moves inward and releases factors that instruct the ectoderm above to become neural tissue.
• Animal cap tissue from a frog embryo, if cultured before gastrulation, becomes skin, but after mesoderm ingression, it becomes neural tissue.
• This suggests the timing of neural fate induction occurs during gastrulation.

The Organizer

• The organizer is a region of the dorsal mesoderm that gives rise to the axial mesoderm in the future animal.

• The organizer releases factors that induce the surrounding ectoderm to become neural tissue.

• Experiments by Spemann and Mangold demonstrated this through transplantation of the dorsal lip of the blastopore, which resulted in a secondary axis in the host embryo.

• In chickens, Hensen's Node takes on the role of the dorsal lip of the blastopore as the organizer.

• Cells going in through Hensen's Node form the head mesoderm, foregut, and notochord.

• Cells entering through the streak form other endoderm and mesoderm.

• Hensen's Node functions as the organizer in birds and mammals, analogous to the dorsal lip of the blastopore in frogs.

Neural Induction Molecules

• Expression cloning identified factors that could rescue UV light-treated embryos and form a neural tube.
• Gene products are injected into ventralized embryos (lacking dorsal parts) to identify neural-inducing combinations.
• Noggin is one such mRNA that can rescue ventralized embryos and induce neural tissue, possessing inducing power.

BMP Signaling

• Induction of neural fates involves blocking BMP signaling and activating FGF signaling.
• Noggin, Chordin, and Follistatin block BMP signaling, preventing ectodermal cells from becoming epidermis (skin).
• Blocking BMP activity allows ectoderm to activate neural genes and become neural tissue.
• In higher vertebrates, FGF signaling must also be activated in addition to blocking BMP signaling.
• FGF signaling and blocking BMP signaling promote the induction of neural genes.
• During gastrulation, neural tissue forms from the ectoderm, with mesodermal signals important in vertebrates.

Lateral Inhibition

• Neural progenitors are neural stem cells, but not everything in the neurogenic region becomes a neural progenitor.
• Lateral inhibition is a stochastic process where some cells in the neurogenic region become neuroblasts (neural stem cells), particularly in drosophila.
• Proneural clusters in the neurogenic region express the Asc transcription factor.
• Only one cell per cluster maintains Asc expression, becoming a neural progenitor, and inhibits its neighbors.
• The cell with slightly more Asc inhibits the other cells within the cluster, restricting the number of neural progenitors.
• Inhibition is done through the Notch signaling pathway.
• Asc drives the expression of delta (a transmembrane protein) which activates the Notch receptor on surrounding cells.
• Cells with more Asc and delta inhibit their neighbors, leading to their selection as the winning cell.
• Delta is a membrane-bound inhibitory signal protein, maintaining Asc expression in the winning cell.
• Delta up-regulation in the neuroblast activates Notch receptors, inhibiting surrounding cells.
• Following induction and lateral inhibition, anterior-posterior and dorsal-ventral axes further specify cell identity.

Vertebrate Brain Vesicles

• The forebrain (most anterior) divides into the telencephalon and diencephalon.
• The midbrain is a single vesicle, also known as the mesencephalon.
• The hindbrain (most posterior) divides into the metencephalon and the myelencephalon.
• The hindbrain is also called the rhombencephalon, segmented into eight rhombomeres.
• Posterior to the hindbrain is the spinal cord.

Anterior-Posterior Specification

• In invertebrates, AP identity and polarity are predetermined in the egg.
• A cascade of proteins controls gene expression, dividing the embryo into progressively smaller regions and activating segment polarity genes and homeotic genes (hox genes).
• Segment polarity genes subdivide the insect embryo, defining segment boundaries.
• Hox genes specify the identity of each segment.
• Removing hox genes results in missing structures.
• In vertebrates, hox genes are essential for neuron identity in the neural tube, especially in the hindbrain and spinal cord.
• The Rhombencephalon is split into eight segments (rhombomeres) labeled r1-r8 from anterior to posterior, each with unique characteristics.
• Hox gene mutations impact rhombomere identity and hox genes specify the identity of each rhombomere. Removing the hoxal gene leads to a missing specification of r4 and r5.

Activator-Transformer Hypothesis

• Activators (BMP inhibitors, FGF signaling) induce neural tissue with anterior characteristics that typically become forebrain and midbrain.
• Transformers (RA, Wnt, FGF) transform neural tissue into posterior structures such as the spinal cord and hindbrain and promote posterior over anterior fates.
• Retinoic acid (RA) is a powerful transformer that can cause embryological defects, where adding RA causes the forebrain and eyes to disappear, and larger spinal cords to develop.
• Blocking the RA receptor results in larger eyes and forebrain, with smaller spinal cords.
• Transformers promote posterior identity TFs and inhibit anterior identity TFs.

Transformers

• Transformers regulate the expression of TFs in an antagonistic relationship, such as Otx2 (anterior) and Gbx2 (posterior), which cross-inhibit each other, forming a midbrain-hindbrain boundary.
• The midbrain-hindbrain boundary (MHB or isthmus) acts as a secondary organizer with inducing capabilities and can induce midbrain structures anteriorly and the cerebellum posteriorly.
• Transplanting the MHB to the telencephalon can create ectopic midbrain and cerebellum structures because it secretes organizing factors.

Isthmic Organizer

• Otx2 and Gbx2 cross-inhibit each other.
• Gbx2 promotes the expression of Fgf8, while Otx2 inhibits its expression.
• Fgf8 can lead to expressions of Enl and Wnt1, and these three rule the formation of the midbrain and cerebullum.
• They boundary they form will regulate the formations.

Shh and BMP

• Shh specifies ventral fates, whereas BMP specifies dorsal fates in a concentration-dependent manner.
• Signals will also regulate the polarity around the dorsal-ventral axis.
• Shh is a morphogen released by the notochord and floor plate (ventral) to promote ventral fates.
• Morphogens are secreted by specialized cells, diffusing to create concentration gradients.
• BMP is released by the future epidermis and roof plate (dorsal).
• Shh and BMP act antagonistically.
• Shh induces ventral neural markers in a concentration-dependent manner and is sufficient to induce ectopic floorplate markers (ventral).
• Shh is required for ventral fate specification.
• Removing Shh causes ventral fates to disappear, allowing dorsal fates to expand, that also patterns limbs, lungs, and other organs.

Neurogenic Phase

• Progenitors start acquiring identity along the AP and DV axis and generate neurons.
• Progenitors line the cavity of the neural tube, expanding initially to create more progenitor cells.
• They switch to dividing asymmetrically to generate one progenitor cell and one neuron.
• Many progenitor cells end up "quitting" by generating two glial cells or two neurons.
• More neurons you will have as the progenitors decide to quit and how long their cell cycle is.
• The expansion phase has a low "quitting fraction", when the progenitors decide to start generating glia and stop generating neurons affects the overall process.
• The gliogenic switch occurs during the end of embryonic development and involves lateral inhibition with Notch-delta signaling.

Cerebral Cortex

• Neurons born at the ventricle migrate to their final location.
• Some structures in the neural tube are laminated (layered), while others are not.
• The mammalian cortex is one-layered in structure and consists of six layers formed by glutamatergic pyramidal (excitatory) neurons.
• Inhibitory (gabaergic) neurons, from a different and from the ventral forebrain, source mix with excitatory neurons and are need for healthy brain function.
• Glutamatergic pyramidal neurons migrate on radial glia, which serve as stem cells.
• Radial glia in the ventricular zone produce neurons, that crawl on top of radial glial cells after birth, and migrate radially.
• Glutamatergic neurons undergo radial migration.
• The cortical layers form inside first/outside last and inhibitory neurons follow to get to the sphere.
• Progenitor cells undergo symmetric and asymmetric cell divisions.
• The amount of neurons and glia that a progenitor will generate is regulated by cell length cycle.
• Granule cell precursors migrate over Purkinje Cells and form a secondary zone of neurogenesis: where Granule cells are the most numerous in the brain.

Reeler Mutant

• Reeler is a signal that contributes to the regulation of migration events, and was identified through spontaneous mutation.
• The Reeler Mutant cause motor phenotype issues, widespread disorganization and Purkinje cels of the cerebellum cluster.
• Tells migrating neurons to detach from the radial glial cells.

Cellular Differentiation

• Cell fates are determined by intrinsic and extrinsic factors.
• Some are touch (C. elegans), and some are the ventral cord neurons (Drosophila).
• The neuroblast, the progenitor cell, switches its genetic program that is defined by one of these TFs.
• Mother cells keep the program at time of cell division where NBs divide to creates more neuron.

Neuroblasts

• Neuroblasts (NBs) are precursors of neurons and glia and divide asymmetrically to give rise to neuroblasts and ganglion mother cells (GMCs).
• GMCs divide just once more to give rise to either two neurons or a neuron and a glial cell.
• The the average NB will divide five times, however the range is from twelve to two.
• TFs are are expressed by the NB at the time of birth and will define the identity the GMC.
• In deciding the cells, there is asymmetry divisions and cytoplasmic targeting decide what cells become NB and GMC is the numb factor.

Vertebrate Retinogenesis

• Defined by latitude, longitude and timing
• HOX and AP determine segments
• Combination of the temporal axis that give rise to different GMCs
• Different types of neurons born around the same time
• Early progenitor are very flexible, and do generate late fates

Neural Type

• Specification of photoreceptor types requires intrinsic and extrinsic
• There is dependence on timing of cell birth
• Heterochronic in Crotex can have loss of competence over time

Gradients

• Specify cell fates

Neural Crest

• derived from the dorsal neural tube that migrate for cell types
• BMPs will direct what the progenitor will become.

General Axon

• One gets cut, one gets the axon.
• Repulsive and Attractive can guide axons
• Receptors will trigger changes in their cytoskeleton to Steer axon
• Contact-mediated and repulsion create topographic maps on surface via signaling.
• Netrin: early spinal cord is attracted, and the receptors are what determine function.
• DCC is attractant, and UNC is repulsive.
• Slits are a protein to push axons out of the midline.
• Receptors are initially attractive to come through.