Lecture 8: Ectoderm Neural Patterning

Ectoderm Characteristics:
  - Forms many derivatives critical for development.   - Neural tube and peripheral nervous system formation are complex processes.
  - Surface ectoderm develops into external structures like skin.
  - Neural crest produces various derivatives, including neurons and glial cells.   - Neural tube gives rise to brain, spinal cord, motor neurons, and eyes.

Neural Plate Development:
- A portion of the dorsal ectoderm is specified as a neural plate. - Neural plate develops columnar epithelial cells, leading to the rudimentary nervous system (neural tube). - The early embryo is termed a neurula during this stage of neurulation.

Competence:
- Cells acquire the potential to become neuroblasts.
Specification:
- Cells are identified as neuroblasts, a process that can still be altered.
Commitment:
- Cells definitively become neuroblasts, resistant to inhibitory signals.
Differentiation:
- Cells exit the mitotic cycle and mature into neurons.

Specification Signals:
- Inhibition through BMP antagonists such as noggin and chordin.
- Competence is likely induced by FGF8 from the primitive streak, which promotes early neural gene expression. - If FGF8 is inhibited, the neural plate fails to form, even in the presence of noggin and chordin. - Wnt signaling may restrict lateral spread of the neural plate.

Mechanisms of Neural Tube Formation:   1. Primary Neurulation:
     - Surrounding cells induce proliferation and invagination, pinching off to form a hollow tube.   2. Secondary Neurulation:
     - Involves mesenchyme coalescence into a solid chord that eventually hollows out; the final structure requires joining of both formations.
Ectoderm Division:
  - Primary neurulation divides ectoderm into:
    1. Internal neural tube
    2. Externally positioned epidermis
    3. Neural crest cells generating peripheral neurons, glia, and facial structures.   - Neural plate edges thicken and migrate upward.
Neural Plate Transformation: - Cells of the neural plate extend and converge, resulting in multi-layer thickness.
- Bending occurs in species-specific modes, such as in birds and mammals forming medial hinge points (MHP) that anchor to the notochord and create a furrow at the dorsal midline.

Hinge Development:
- Additional hinge regions include dorsolateral hinge points (DLHP), which anchor to the surface ectoderm, contributing to neural plate height reduction and wedge shape formation. - Microtubules and microfilaments facilitate the shape alterations of these hinge points.

Closure Process:
- The neural tube undergoes closure, adhesion, and merging of structures, with neural crest migration either concurrently or during tube closing. - Anterior closure occurs before posterior closure, creating anterior and posterior neuropores. - Closure in chicks proceeds from anterior to posterior, while in humans, neural tube initiation occurs at different sites, ultimately merging. - Failure of closure can lead to neural tube defects such as spina bifida or anencephaly, influenced by genetic and environmental factors (e.g., folic acid, cholesterol).

Post-Closure Events:
- Following closure, the neural tube separates as a closed cylinder from the ectoderm through cadherin expression changes. - E-cadherin is expressed in the ectoderm, while N-cadherin and N-CAM start expression in the neural tube, breaking adhesion properties. - Injecting N-cadherin into epidermal cells results in separation failure.

Secondary Neurulation Role:
- This process comprises mesoderm condensation that forms a solid chord, later hollowed out, occurring in the posterior neural tube beyond lumbar regions. - It signifies a continuation of gastrulation dynamics.

Regions of the Brain:
  - The anterior neural tube differentiates into three primary vesicles:     1. Prosencephalon (forebrain)
    2. Mesencephalon (midbrain)
    3. Rhombencephalon (hindbrain)   - Optic vesicles arise from lateral extensions of the forebrain prior to posterior tube closure.
Subdivision of Vesicles:
- The prosencephalon is divided into: - Telencephalon (forms cerebral hemispheres) - Diencephalon (thalamus and hypothalamus formation; also includes retina). - The five secondary vesicles are: 1. Telencephalon -> Adult derivatives: olfactory lobes, hippocampus, cerebrum. 2. Diencephalon -> Adult derivatives: retina, epithalamus, thalamus, hypothalamus. 3. Mesencephalon -> Adult derivatives: midbrain. 4. Metencephalon -> Adult derivatives: cerebellum, pons. 5. Myelencephalon -> Adult derivatives: medulla, spinal cord.

Segmentation Patterns:
- The rhombencephalon undergoes periodic segmentation into units known as rhombomeres. - Cells within each rhombomere interact without intermingling with neighboring segments. - Cranial nerves are derived from rhombomeres, linking their segmentation to nerve differentiation.

Vesicle Enlargement Mechanisms:
- Ongoing openings between brain and spinal cord facilitate the development of internal pressure, crucial for brain growth (e.g., chick growth 30-fold in two days). - Removal of occlusion drastically affects the growth and neuronal population.

Polarity Establishment:
  - The neural tube exhibits distinct dorsal-ventral polarity:
    - Dorsal region is responsible for receiving sensory neurons.
    - Ventral region projects motor neurons, with intermediate areas housing interneurons.

Signal Gradients:
- Two key signaling centers are: 1. Notochord, producing Shh (Sonic Hedgehog). 2. Epidermis, inducing BMP4 and BMP7. - These signals create a gradient leading to dorsal-ventral differentiation in neuronal tissue.
Transcription Factors Induction:
- The concentration gradients of Shh and TGFβ signal for a sequence of transcription factors that dictate neuronal fate (e.g., motor neurons vs. interneurons).

Neurons Formation:
- Neurons develop dendrites to receive signals and an axon to transmit signals. - Axonal growth is facilitated by elongation and retraction mechanisms aided by cytoskeletal elements, forming growth cones for pathfinding.

Epidermal Layer Formation:
- Epidermis transitions to two-layer thickness:
- Outer periderm, shed as differentiation continues. - Basal layer evolves to form spinous and granular layers, initiating keratin production.
Epidermal Growth Regulation:
- Basal cells produce TGF-α as an autocrine growth factor; human cell transition from basal to surface occurs over eight days, while psoriasis accelerates this to two days, indicating overexpression of TGF-α.

Follicle Induction:
- Hair follicle development initiates from dermal mesoderm condensation, directed by dermal fibroblasts. - Signals such as Wnt promote FGF10 expression, leading to hair placode formation.

Shh and BMP Interaction:
- Wnt interactions stimulate Shh expression for placode formation while BMPs repress it.
- The presence of specific signaling pathways determines the success of follicle development and the placement of hair follicles in the ectoderm.