2 - Development Of CNS Flashcards
Name 2 disorders caused by Folic Acid deficiency during development
Spina Bifida - failure of posterior end of neural tube to close (spinal cord)
Anencephaly and Holoprosencephaly - failure of the anterior neural tube to close. Lacks forebrain, so usually results in death
Describe the process of Neuralation
- Gastrulation forms the ectoderm, mesoderm, and endoderm
- Notochord arises from mesoderm and defines the midline/axis
- Mesoderm secretes BMP to induce formation of epidermis from ectoderm
- Notochord secretes Chordin and Noggin, which inhibit the action of BMP on ectoderm surrounding the notochord, allowing the ectoderm to follow the default pathway - Neural Induction
- Lateral margins of neural plate (ectoderm above notochord) fold inward to form the neural tube, starting from the middle and moving anteriorly and posteriorly. The Neural Floorplate and Crests are important for signaling
- The Neural Crests pinch off the neural tube, eventually becoming sensory ganglia, cartilage/bone, and other cell types in the PNS
Explain Dorsal/Ventral Patterning
Neural Floorplate (Ventral) produces Sonic Hedgehog (Shh), which induces motor neuron differentiation
Neural Roofplate (Dorsal) produces BMP, which induces sensory neuron differentiation
RA and FGF signaling also play key role in affecting gene transcription for neuron differentiation
Developmental defects in Shh Patterning
Holoprosencephaly - Lack of forebrain due to absence of Shh signaling and dorsal/ventral polarity is disrupted
Medulloblastomas and Basal Cell Carcinomas - Shh disruption can cause these cancers because it also regulates proliferation
Cyclopia - Shh disruption alters polarity of head, resulting in a single eye in the middle of the face
Explain Anterior/Posterior Patterning
Leads to formation of spinal cord, rhombencephalon (pons, medulla), mesencephalon (midbrain), and prosencephalon (thalamus, retina, forebrain)
Combinations of Hox genes specify the segment identity along the A/P axis in the spinal cord, medulla, and pons. Proteins encoded by Hox genes are powerful transcription factors.
NO Hox genes for the forebrain and midbrain!
Explain the difference between Symmetric and Asymmetric Proliferation
Symmetric - Neural stem cell divides and differentiates into 2 identical neurons
Asymmetric - Neural stem cell divides but only 1 differentiates into a neuron, the other remains a neural stem cell
Describe Cell proliferation and migration in the CNS
Ventricular zone (strip of neural stem cells and neural progenitor cells surrounding the ventricles) is the site of NSC division and differentiation. The cells then migrate to the cortical plate.
1 - Neural Induction produces NSCs
2 - (Early development) Symmetric cell division yields 2 NSCs (capable of self-renewal). These divisions increase the size of the brain, and the ventricular zone expands laterally.
3 - (Mid-development) Asymmetric cell division yields 1 NSC and 1 Neural Progenitor, which will give rise to neurons and glia
4 - (Late development) Symmetric division of NSC yields 2 Neural Progenitors so that NSCs eventually disappear
- Precursor cells also divide symmetrically and asymmetrically
- Neurons are generally made first, glia come later in development
Describe regulation of Neural Stem Cell differentiation
Inhibition of Notch and activation of bHLH transcription factors signal creation of neural precursors from NSCs.
Notch signaling through the ligand Delta requires cell-cell contact.
1 - Neural Progenitor Cell up regulates Delta and bHLH because of low Notch activation due to low Delta being secreted by the neighboring Neural Stem Cell
2 - The increased Delta from the NPC hyperactivates Notch on the neighboring NSC, causing inhibition of Proneural gene transcription by the NSC (including inhibition of Delta production), keeping the NSC in its pluripotent state
-Astrogliogenesis is Notch-dependent, but Oligodendrogenesis is not. both occur via bHLH inhibition
What accounts for the dramatic increase in brain size after birth?
Elaboration of dendritic connections.
The basic shape of the brain is fully formed at birth and the vast majority of neurons are already generated.
Explain Impacts of drugs on brain development
Fetal Alcohol Exposure - dramatic but non-specific inhibition of development
Drugs - decrease in size of grey matter in the cortex and caudate
Explain neurogenesis migration
Cortex forms in an inside to outside manner. Layer closest to the ventricular zone forms the earliest
- Cells migrate to the pial surface, so newers cells push down the older cells to get to the pial surface (at the cortical plate)
- Radial migration of neurons depends on radial glia, which have a process that extends from the ventricular zone to the pial surface. neuron lasts migrate along these radial glia fibers until they reach the pial surface, where they detach from the fiber
- Radial glial cells are NSCs that eventually become neurons
- Reelin (ECM protein) regulates radial migration
-Interneurons migrate tangentially over long distances into the developing cortex, derived from Medial and Lateral Ganglionic Eminences (MGE/LGE) so they cannot migrate radially. Mediated by DLX1, DLX2, and Mash1 transcription factors
What is the primary function of Reelin and what happens if it is mutated?
Reeling regulates the radial migration of neurons from the ventricular zone to the pial surface
Mutant Reelin results in Lissencephaly - an inside-out brain
