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• Early neural development involves a subset of ectodermal cells being instructed to form neural tissue.
• Cell identity is further specified along the anterior-posterior and dorsal-ventral axes, leading to the identification of specific neural cell types.

Gastrulation and Neural Tissue Induction

• During gastrulation, early embryo cells arrange into three germ layers, with the ectoderm specified to become neural tissue and skin.
• All nervous system components originate from the ectoderm, developing into the neural tube, which gives rise to the central nervous system (CNS) and peripheral nervous system (PNS).
• Induction of the ectoderm happens during gastrulation.
• Factors released by the dorsal or axial mesoderm induce the ectoderm above it to become neural tissue.
• When gastrulation begins, the induction of neural fates happens.
• The Spemann-Mangold organizer is responsible for telling part of the ectoderm to become neural tissue.
• The Spemann-Mangold organizer is a region of the dorsal mesoderm that releases factors, directing surrounding ectoderm to become neural tissue.
• Transplanting the dorsal lip of the blastopore makes the host embryo grow two brains and two spinal chords

Hensen's Node

• Hensen's node in chickens assumes the role of the blastopore.
• Axial mesoderm cells go into Hensen's node and release factors that promote neural tissue induction above them.
• Hensen's node functions as an organizer in chicken/mammals/birds, while the dorsal lip of the blastopore serves the same role in frogs.
• Certain factors can rescue embryos treated with UV light

Noggins, Chordin, and Follistatin

• Some combinations of gene products of mRNAs can artificially induce neural tissue.
• mRNA-NOGGIN can rescue ventralized embryos without injection.
• Noggin has inducing power
• Chordin and follistatin have similar activity to Noggin
• Noggin, chordin, and follistatin block BMP signaling.
• BMP signaling pushes ectodermal cells to become epidermis and blocking their activity allows ectoderm to turn on neural genes.
• Induction in higher vertebrates promotes future neural tissue.
• Neural tissue is induced during gastrulation.
• The nervous system is derived from ectoderm.
• Signals from the mesoderm are important for neural induction in vertebrates.
• Neural fates is mediated by blocking BMP signaling and activating FGF signaling

Lateral Inhibition and Cell Identity

• Only select cells within the prospective neurogenic region become neural progenitors or neural stem cells.
• Few cells become neuroblastoma through a stochastic process.
• Asc drives expression of transmembrane protein delta which activates notch receptor
• More Asc = more delta, which can inhibit neighbors
• After induction and lateral inhibition, cell identity is further specified along the anterior-posterior and dorsal-ventral axes.

Brain Regions

• The forebrain (prosencephalon), the most anterior part of the brain, is divided into the telencephalon (cerebral hemispheres) and the diencephalon (thalamus, hypothalamus, retina).
• The midbrain (mesencephalon) is a single vesicle within the neural tube, containing the tectum (superior colliculus) and inferior colliculus.
• The hindbrain (posterior) is divided into the metencephalon (pons, cerebellum) and myelencephalon (medulla), also called rhombencephalon due to its division into eight rhombomeres.
• The spinal cord is posterior to the hindbrain.

Anterior-Posterior Specification and Hox Genes

• Maternal factors is what determines the anterior-posterior identity and polarity.
• In invertebrates, transcription factors (TFs) subdivide embryos into smaller regions.
• Segment polarity genes subdivide the embryo into segments by defining their boundaries.
• Hox genes determine the identity of each segment.
• In drosophila one series of Hox genes is divided into 2 clusters.
• These clusters come together in vertebrates and duplicates into 4 full complements of ancestral hox genes

Rhombomeres

• The human rhombencephalon is segmented into 8 rhombomeres
• Each rhombomere has distinct characteristics originating different neurons and cranial nerves
• Hox genes specify the identity of each rhombomere through specific combinations of Hox gene expression.
• Only Rhombomere 1 has no expression of hox genes (default state)

Anterior and Posterior Transformation

• Activators induce neural tissue.
• Transformers, like RA, transform part of the neural tissue to more posterior structures.
• Retinoic Acid (RA) promotes posterior fates at the expense of anterior fates
• Greater retinoic acid (RA) leads to bigger spinal cords and no forebrain, blocking RA leads to bigger forebrains and smaller spinal cords.

Otx2 and Gbx2

• Examples of transcription factors that promote anterior vs posterior identities are Otx2 and Gbx2.
• Otx2 is expressed in more anterior parts of neural tube, and promotes anterior fates; if it is removed, the forebrain and midbrain go missing.
• Otx2 and Gbx2 mutually inhibit each other, establishing a sharp boundary between anterior and posterior to give the midbrain-hindbrain boundary (MHB) which is also known as the isthmic organizer

Midbrain-Hindbrain Boundary (MHB)

• The MHB is a secondary organizer that can induce ectopic cerebellum or midbrain.
• Tiny fragments tissues can release factors that tell surrounding tissue to become cerebellum & midbrain
• Expression of Otx2 and Gbx2 is what sets the boundaries of the MHB

Polarity along the DV Axis

• Shh is the signal that promotes polarity and different fates along the dorsoventral axis.
• Shh acts as morphogen to promote ventral fates.
• Shh is released by notochord and floor plate, acting in a concentration-dependent manner to promote different fates along the ventral side of the spinal cord.
• BMPs, released from the future epidermis promote dorsal fates.
• Shh is sufficient to promote ventral fates because if there are more Shh there will be more ventral fates, more floor plate, motor neurons etc
• Shh is required for specification of ventral fates

Division

• Initially, Progenitor cell create more progenitor cells because there is a limited amount of progenitors
• Next they asymmetrically divide in order to create either a neuron or progenitor cell
• Lastly, a lot of progenitors end up quitting (through fractionation)

Neuronal Migration

• Neurons born at ventricle have to migrate to their final location
• Mammalian cortex is organized into layers of glutamatergic pyramidal neurons & inhibitory GABAergic interneurons.
• 6 layers are formed by glutamatergic neurons, except layer 4, which has excitatory neurons Inhibitory neurons from different sources mix with excitatory neurons to keep a balance between excitation and inhibition
• Excitatory neurons migrate radially from the ventricle.
• Radial glial cells act at tracts for neurons, going from inside -> outside _ Radial glial cells produce neurons, those neurons then have to migrate outwards to go to the surface
• Inhibitory neurons are from a different place which is the Media Ganglionic Eminence (MGE).
• Inhibitory neruons travel tangentially while excitatory neurons are going from inside to outside

Summary of Neurons

• Neural progenitor cells originate in the ventricular zone
• There are divisions between symmetric and asymmetric cells in the process
• Progenitor cells regulate neural and glia by length of cell cycle
• The cortex develops from inside to outside
• Radial glia serves as tracks for migrating neruons
• Neural cells can be transported from cell to cell either by tangential or radial migration

Neural Progenitors

• There are intrinsic limits to the number of cell divisions.
• Extracellular signaling factors promote or inhibit cell division
• Granule cells of cerebellum has progenitors that are born in rhombic lip, migrate tangentially, and generate neurons

Rellin

• Mutations effects the clustering of purkinje cells
• Cell fates are determined due to intrinsic and extrinsic factors
• in C. Elegans it starts at the unc-86

Drosophila and Differentiation

• Sequential experiments of TFs what determines the types of ventral cord neurons
• Progenitor cells switch genetic programming that id defined by on of the TFs
• Born mother cells will keep programming as they undergo cell division
• Divisions are asymmetric, going Nb and GMC1, where GMC1 divides into 2

Neuroblast Differentiation

• Identity of Nbs is what determine the latitudes and timing
• Hox gene has differences between what progenitors become
• DV axis discussed DPP and diff TFs

Vertebrate Retinogenesis

• There are different types of neurons at retina
• What we retinogenesis is similar to what is seen in the cortex
• Experiments are done where early progenitors act like late progenitors

Cortical Competence

• If the get progenitors that are move to an older animal then they get converged and start generating layers 2 and 3
• Early progenitors will behave the same as the layers and generate layers and 3 neurons

Late Early Heterochronic Process

• Theshh promote the expression of Class II TFs and Class I progenitors
• TFs are expressed on both sides of the cord and cross inhibit the pair
• Extrinsic factors are important
• Neural crest cell migrate long stance to form cellular structures
• What determines which neural cells are supposed to become are based on which ones come across the migratory path
• BMPS becomes synaptically

Summary of Neural Crest Cells

• Lineage helps extrinsic and intrisic factors, leading to cell determination of neural tissues
• Timing of birth affects neuronal differentiation.
• Shh and Bmp regulate expression of transcription factors along the progenitor cells determine the spinal cord.
• Expression is what the BMPs become for neural structures
• More factors get created on growth cones

Growth Cone Development

• Guidance receptros lead to steer the axon
• Semaphorins secrete 3a which can form graidents, repelling axons =- Topographic maps in the retinas are what help determine initial stages
• Netrin act as a attractant for the spinal cord.
• Receptors: Robo
• Commissureless: turns Robo one and off

• Essentially: The process by which it occurs • They act by promoting assembly and stabilization of actin or destabilization of actin to make civilizations