Developmental Neurobiology

Comparative Neurodevelopment and Neural Stem Cells

• Metazoan tissues are layered; these layers are critical for differentiation, giving rise to various tissues, including the nervous system.
• These layers originate from the egg cell through divisions and rearrangements.
• Nervous system development commences once the three primary germ layers are established
• Neural induction does not occur in a vacuum.

Early Embryonic Development

• Zygote develops into an eight-cell stage through cleavage
• Blastula is a hollow ball of cells containing a blastocoel
• Gastrulation involves cells invaginating and migrating into the hollow blastula
• Gastrula is the stage after blastula, featuring ectoderm, mesoderm, and endoderm
• Germ layers include ectoderm, mesoderm, and endoderm, all formed in the early embryo

Caenorhabditis Elegans

• Studied for a simple structure (thousands of cells), fast reproduction, and transparency
• Possesses a hypodermis, similar to other animal's epidermis, but a structure
• Simple NS. Composed of 302 neurons and 56 glial cells; neurons are organized into nerve cords.
• Simple digestive system, movement via longitudinal muscles
• Neuron numbers can be predicted due to the stereotypical position and division of the cells
• Fertilized egg divides into AB (hypodermis/nervous system) and P1 (body/muscle/gut/gonad) populations. AB is larger.
• In the 4 cell embryo, ABa is anterior, ABp posterior
• In the 8-cell embryo, the mesendo divides into mesoderm and endoderm
• Post-gastrulation, AB progeny spreads to produce hypodermis
• Specialization occurs after gastrulation, motor neurons locating ventrally, sensory neurons dorsally

Drosophila Melanogaster

• Is easy to breed and has a short life span
• Complete nervous system comprises brain and spinal cord
• The nervous system is located ventrally
• Early stages establish anterior-posterior and dorsal-ventral axes
• Ectoderm is dorsal; neurogenic regions lateral, mesoderm ventral
• No cells initially; it is a syncytium, nuclear divisions without cell division
• Cellularization occurs during gastrulation
• Size increases during gastrulation, pushing ectoderm and neurogenic regions down and mesoderm inside
• Cellularization creates cells composing epidermis, gut, and neuroblast
• Nervous system is ventral due to lateral push → neuroblasts fuse into ventral nerve cord (laminization)
• Anterior-posterior axis differentiation creates brain and spinal cord
• Neurogenesis: ectoderm neurogenic progenitors enlarge and are squeezed (delamination).
• Each squeeze gives rise to a neuroblast, then ganglion mother cells (GMCs)
• Each GMC generates a neuron/glia pair in a regulated manner over time
• Anterior-posterior axis molecules and signaling dictate delamination; anteriorly needs splitting into two encephalic vesicles

Vertebrates - Xenopus Laevis

• Has an egg with animal and vegetal poles; the former becomes the embryo, the latter provides nutrients and energy
• Formation of the blastula and blastocoel
• After gastrulation, blastopore forms, creating the involuting marginal zone (IMZ), part of the ectoderm that migrates
• Blastopore is opposite the entrance of the spermatocyte
• The first migrating cells determine the embryo's ventral part, determining the anterior-posterior axis
• Migration also establishes mesoderm, crucial for neural plate induction on overlaying ectoderm
• First IMZ cells make the head, mesoderm for brain differentiation, later IMZ cells make the spinal cord

The Neural Plate

• It is induced by the mesoderm and is triggered by the notochord
• It invaginates to form the neural tube
• Neural crest cells from the groove become neurons and glial cells of the peripheral nervous system
• Neural tube lies dorsal to endoderm; induction of the neural plate happens dorsally
• Ectoderm becomes the skin
• Notochord is anterior to the neural tube, forms bone, including vertebrae incorporating the neural tube
• Blastopore is inducer and organizer

Zebrafish

• Has a yolkier egg
• Blastomeres divide at the animal pole forming the epiboly which includes the vegetal pole
• At 50% epiboly a shield is created, marking gastrulation's start
• Gastrulation starts migration, forms mesoderm
• Animal has an enveloping layer (ectoderm) and yolk syncytial layer (endoderm)
• Migration occurs under epiblast on the yolk syncitial layer forming mesoderm (hypoblast). The direction is towards the animal pole again
• Blastopore is between mesoderm and neural plate
• First migrating cells form the ventral part (head).
• Neural plate forms on the shield from ectoderm
• Ectoderm continues migration until the vegetal pole is encompassed and there is 100% epiboly

Chicken

• There isn't a balstula, instead there is a blastodisc because of high yolk content
• There's migration of cells within the blastula towards the primitive streak (groove), the active migration site
• Migration from lateral blastodisc migrates in the groove towards the lateral, comprehending the neural plate and tube as the ectoderm covers
• Endoderm is the contact between the embryo and the yolk
• Hensen’s node (posterior primitive streak) is analogous to dorsal lip of blastopore, drives migration inside and forms mesoderm, inducing neuroectoderm There appears somites at early stages

Mammalian

• There are no poles because nutrients are provided by the mother.
• In the blastula, inner cell mass develops embryo, trophoblast forms placenta for uterine implantation
• After implantation gastrulation occurs forming three layers, primitive streak (anterior-posterior), and the neural tube (brain and spinal cord with somites)

Induction of Neuronal Differentiation

• Many experiments to comprehend differentiation
• Ectoderm transplanted from pre-gastrula embryos differentiates only into epidermis
• Ectoderm transplanted from post-gastrula embryos is committed to becoming neural tissue
• Transplantation of blastopore's dorsal lip into another frog creates a new, fully formed animal
• Blastopore acts as an organizer of the anterior-posterior axis creating entire neural tube w/ brain
• Nervous system is induced in both the cells in the introduced tissue and the host animal. It is also able to induce a nervous system from host cells.
• Mesoderm transplants can organize AP axis and induce the ectoderm of the host into a new neural plate then brain and spinal cord
• Interaction of multiple layers required for full embryo; mesoderm drives rest's differentiation

Polarity and Segmentation

• Specialization and regionalization occur in the nervous system development
• First differentiation step is the anterior-posterior axis, occurring early when the fly egg is polarized
• Anterior pole expresses Bicoid, posterior Nanos; both are mRNAs translated after fertilization, controlling expressions binding on DNA
• Bicoid/Nanos levels determine gap gene expression and split bicoid.
• Gap genes control striped pattern via pair-rule genes, splitting AP axis smaller.
• The pair-rule genes control segment polarity genes, definesAP.
• The embryo divides into decreasingly sized regions
• Next step is segment-specific genes: homeotic (HOX)
• HOX genes discovered by mutant studies
• Mutated Ultrabithorax causes two pairs of wings produced
• Mutated Antennapedia transforms leg into antenna
• Knocking out HOX genes leads to nearly identical body region
• HOX genes are important for the anterior-posterior axis and segmentation Chromosomes arranged in linear array of two clusters expressing along AP axis
• Genes are activated to differentiate
• 8 genes in antennapedia (ANT-C) and Bithorax (BX-C) complexes, encoding for homeodomain transcription factor activating the pattern factor
• Homeobox clusters of flies are in vertebrates
• Higher order animals have similar additional genes to compensate for mutations

Hindbrain Development

• Hindbrain develops into: cerebellum, brainstem, pons, medulla oblongata
• Cerebellum function is motor coordination, posture, and cardiac etc
• Brainstem deals w/ breathing, heartbeat, BP
• Pons is chewing/swallowing, the breathing frequency
• Medulla Oblongata regulates breathing and heart rate
• Hindbrain patterns segment formation like in flies
• Hindbrain composed of rhombomeres (R1 to R8).
• Rhombomeres give rise to repeating neuron differentiation sets of motor neurons Rhombomeres are generated by paralogous gene group, the pattern being in all vertebrate
• Hoxa1 null mice have affected R4 boundaries
• Mutations do not equal phenotype changes like Drosophila, as the gene appears in numbers
• Mutation size increases phenotype.

Organizer and Neural Inducers

• Induction is when some cells evoke response
• Dorsal blastopore transplanted ventrally
• Invaginates, develops notochords, induces neural tube from the host ectoderm, and a secondary embryo grew
• Organizer by organizing the creation axis,
• Animal half becomes neural tissue and the endoderm, vegetal makes the endoderm
• Mesoderm is the bone and muscle, around the equator
• Experiments in animal poles do not become mesoderm
• Vegetal pole additions allow mesoderm, directs the vegetal conjunction differentiation The transcription would increase expression.
• Noggin, Chordin, and Follistatin form structures, then retinoic acid, wnts, and fgfs transfer themselves.

Retinoic Acid

• Is a teratogen (birth defects, brain stuff)
• Cell enters memberane and becomes the RAR complex, hitting RARE and the target elements
• High concentrations leads the development, whereas the rest of Hox inhibits the exposure
• RA is driven from the expression in anterior embryo and in posterioly form
• Gradients increase concentrations, for posterior development leading to creation The mesoderm synthesizes that lies by the neural tube
• Nerve activation requires differentiation in the patterning of expression. In vacuum, the systems does not develop.

Wnt Signaling

• Many molecules act by binding receptors.
• Ligand bind occurs by events occurs, from transcription into the pathways.
• Enhancers and inhibitors differ signaling.
• Dkk-1 is an inhibitor that leads the frog to active head.
• Antibodies and tail parts can get damaged
• Co-inhibitor Wnt BMP gives brains.
• Low Levels of Dkk affects the heads The Wnt is gradient, strong in tail, face in head

Fgf Signaling

• Many factors differe from the effects.
• It can be induced by lows and form
• Dkk otx2s and other components of axis implement

Dorsal-Ventral Polarity

• Spinal chord has polarization
• Motor ventral horns in the horn and dorsal horn

Dorsal-ventral gradient

• The polarity is upon the notochord
• Creates ectopic motor neurons to induce, not sensory ones
• Split neural tube to transcriptional gene is
• Expresses Shh in the notchord, and specifies the expression, and occurs after, of floorplate.
• Adding Shh makes changes

Forebrain Development

• The Hox expression at the boundary of the forebrain, for induction of diff genes as relates to problems.
• Transplant the experiment to model, and explaiend with model
• Two genes explain, with two hemispheres separate segments, but tandem.
• Dorsal-Ventral also created dorsal ventrally
• Transcription has fundamental class for devleopment and more There is a lot of factors to affect in the time, and all are cortigogenesis

Development of Cerebral Progenitors - Proliferation

• Tube front is forebrain, presenting enlargement, devisions and these divisons generate glutamate
• Cortal comes other from, differentiation, and boundary is a limit.
• There few difference with brain at 8 weeks in development

Further Development

• However, In humans, there huge and mice less, but other differences between mice and humans.
• Cells keeps growing and give other to gila There are some molecules and factor that perform more different function, liquid axes from the folding They has the ventricular zone (faces the surface), the is composed of the cells.
• The new nurons accumatue, step the wave of it will been developed.

Further markers

• The are outside composted, plate and spinal, are going to be generated, and these that what and when that there develops
• For Cycle Cell, from active splicing and duplicaiton and are split
• The this is injected in the cell and know by bodies.
• Cyctical G1 is here to it into the differation The can what

Early Developmet

• Neoroepielia are the mondlater and on th apical surface.
• Migration, radial, and in order are

Further cell stages

• They are tight and aderent and important for difereation and the
• There asynachronsis cells and complete. -The and
• we new they to all them

Comparison of nervous system development in Drosophila and vertebrates, including neuroblast formation, cellularization, and regional specification.