Lecture 9 Flashcards
Explain neural tube stem proliferation
- Neural tube stem cells give rise to CNS nerve cells, astrocytes and oligodendrocytes
- Replication in ventricular zone
- Stem cells migrate through neural tissue
- Daughter cells remain to form progeny cells or migrate out to form neurons/glial cells
Formation of radial glial cells
Neuroepithelial cells:
- Earliest form
- Divide symmetrically to expand stem cell pool
Early radial glia
- Derived from NECs using transcription factors such as FOXG1, LHX2
- Ventricular to pial surface
Late radial glia
- Committed progenitors appear
nlPC -> Neurons
alPC -> Astrocytes
olPC -> Oligodendrocytes
Formation of neural tube
- Middle of embryonic day 20 - continues towards each end
- Openings at each end are the anterior (cranical) and posterior (caudal) neuropores
- Anterior neuropore closes day 25
- Posterior neuropore closes day 27
What are somites?
Balls of mesoderm that mature into segmented axial skeleton
Each pair added sequentially from head->tail down length of embryo
How is the Wnt signalling pathway involved in neural signalling
Wnt inhibitors - Dickkopf, Cerberus, Frzb, IGF are made from dorsal anterior mesoderm and organiser
Wnt involved in formation of anterior/posterior and dorsal/ventral structures in early nervous system
Canonical Wnt signalling
- Passes signals through cell surface receptors e.g. Frizzled to control DNA expression
- Axin/GSK/APC destruction complex promotes B-catenin degradation
- Stimulation of Dishevelled prevents B-catenin destruction
- B-catenin binds TCF/LEF instead of Groucho to cause constant developmental gene expression
Wnt and BMP in spinal cord and head/brain development
Both Wnt and BMP are involved in the development of the spinal cord and head/brain
BMP inhibited by noggin, chordin, and follistatin
Wnt inhibited by IGF, Cerberus, Dickkopf, and Frzb
FGF and RA and anterior-posterior patterning
FGF made at posterior and degraded at anterior
RA made by central mesoderm
FGF, RA and Wnt signalling all regulate Hox gene expression
Hox at each segment specifies anterior-posterior identity
Brain development from neural tube
Anterior part of neural tube divides rapidly to form three primary vesicles (fore/mid/hind brain)
Part of forebrain curls up and around - becomes cerebral cortex
Posterior part forms spinal cord
What elements of brain are the fore, mid and hind forming?
Forebrain - Cerebral cortex, underlying white matter, corpus callosum, basal ganglia
Midbrain - Vision, hearing, motor control, sleep/wake cycle, arousal, temperature
Hindbrain - Medulla/pons/cerebellum
Medulla - Deals with autonomic functions of breathing, heart rate, blood pressure
Pons - Part of brainstem that relay signals to cerebellum from forebrain. Eye movement, taste, swallowing etc
Cerebellum - Posture and balance
6 layers of neocortex
- Molecular layer- few neurons, mostly dendrites/axons
- External granular layer - Small pyramidal/stellate neurons for local processing
- External pyramidal layer - Medium pyramidal neurons/interhemispheric communication via Corpus callosum
- Internal granular layer - Tightly packed stellate cells (primary input from thalamus)
- Internal pyramidal layer - Large pyramidal neurons which output to brain stem and spine
- Fusiform layer - Fusiform neurons (output to thalamus/subcortical structrues
Inside out sequence of cortical layers
- First cohort of post-mitotic neurons moves from ventricular zone to pial surface to form pre plate
- First migration wave of cortical plate neurons arrives in the middle of preplate, splitting into marginal zone, preplate and subplate
- More cortical plate neurons arrive in an inside out sequence (earliest form layers form layer 6, last-born layer 2)
How do you visualise neurons
Using intermediate filament proteins/cell markers
Neural stem cells express nestin in early developmental stages of CNS and PNS
Nestin downregulates during differentiation - replaced by intermediate filaments
Immature glial cells express vimentin
Mature nerve cells express neurofilament proteins
Mature glial cells express glial fibrillary acidic protein
IF proteins used as cell-specific markers
Neurons migration
Neurons originate in the subventricular zone, where progenitor cells divide either symmetrically (expanding the pool) or asymmetrically (producing neurons).
Radial migration guides excitatory neurons along radial glia to the cortical plate, forming the layers of the cortex.
Tangential migration is used by inhibitory interneurons to move across the cortex from different origins.
Permissive and restrictive factors in the cortical and subpial zones, respectively, regulate neuron positioning and migration limits.
Disruptions in these processes can lead to cortical malformations and neurodevelopmental disorders such as epilepsy or schizophrenia.
Reelin
- Extracellular-matrix associated glycopreotein
- Cajal-Retzius cells in marginal zone light up when developing mouse brain cortex is immunostained with an antibody to reelin
Reelin receptors
Binds:
- Very low density lipoprotein receptor
- Apolopoprotein E receptor type 2
- Amyloid precursor protein
- Integrin receptors
Disabled 1 binds cytoplasmic tails of above receptors and is phosphorylated
Downstream signalling kinase cascades cause change in gene expression and neuron surface properties, causing migration
Reeler Null and Scrambler mice
Reeler null and scrambler (DAB1 null) mice fail in having preplate neurons split into marginal zone, cortical plate and subplate
Staining for chondroitin sulphate proteoglycans labels preplate neurons
Scrambler doesn’t have Dab1 so can’t respond to Reelin
Human reelin mutation linked to lissencephaly and autism
Adult neural stem cells
Retained in human brain
Dentate gyrus of hippocampus (subgranular zone) - involved in memory?
Lining of lateral ventricles (subventricular zone) - move to olfactory bulb
