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An overview of nervous system development How are all the different regions and cell types specified? How do they arise in the correct areas? How do all.

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Presentation on theme: "An overview of nervous system development How are all the different regions and cell types specified? How do they arise in the correct areas? How do all."— Presentation transcript:

1 An overview of nervous system development How are all the different regions and cell types specified? How do they arise in the correct areas? How do all these regions/cell types get connected together?

2 Patterning, proliferation and neurogenesis

3 Specification of cellular identities

4 Wiring

5 Processes to consider:  Induction of the nervous system  Neurulation (formation of the neural tube)  Patterning of major axes  Proliferation  Establishment of cell fates  Cell migration  Axon guidance  Synaptogenesis  Cell death  Synaptic refinement  Myelination References: Jessell and Sanes (2000); Kandel, Jessell and Schwartz, Principles of Neuroscience

6 Clinical relevance  Birth defects  Psychiatric disorders  Regeneration  Stem cell therapeutics

7 Proliferation and Neurogenesis Amount of proliferation controlled by amount of asymmetric cell division When a progenitor cell divides does it make: - Two progenitors? - One progenitor and one neuron? - Two neurons?

8 Differential rates of proliferation

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10 Microcephaly  Small head size (small brain)  Moderate to severe mental retardation  Seizures (rare)  Genetically heterogeneous (six loci identified)

11 Chuas or “rat people” Many found at shrine to 17th century Sufi saint 1st cousin marriages - common in British Pakistani community too

12 Can the study of microcephaly tell us anything about control of proliferation and evolutionary expansion of the neocortex?

13 MCPH5: autosomal recessive, linked to chromosome 1q31

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15 Principle of linkage analysis Variants near each other on the same chromosome (“linked”) tend to be inherited together. The co-inheritance of a neutral molecular marker with a disorder implies the mutant gene is near that marker. Recombination in meiosis:

16 Bond et al., (2002) Nature Genet. 32: 316 MCPH5 mapped to ASPM gene Homologous to abnormal spindle (asp) gene in Drosophila Mutations lead to truncated protein

17 Expression of ASPM in developing mouse brain Ventricular zone

18 Neurogenesis and migration in the cerebral cortex

19 A number of other genes that cause Microcephaly have also been identified:  MCPH1: Microcephalin - control of mitosis (Jackson et al., (2002) Am J Hum Genet. 71, )  MCPH3: CDK5RAP2  MCPH6: CENPJ - both involved in chromosome segregation in mitosis (Bond et al., (2005) Nat Genet. 37, 353-5)

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22 How do mutations in genes controlling mitosis lead to microcephaly? Aspm mRNA expressed at early stages: - Divisions are symmetric - Progenitor pool expanding Aspm mRNA downregluated at later stages: - Divisions are asymmetric - Neurons being generated

23 Symmetric divisions at early stages generate two neuroepithelial progenitors - expand pool of progenitors Asymmetric divisions at later stages generate one postmitotic neuron and one progenitor - as each progenitor can only generate a limited number of neurons this eventually depletes pool of progenitors and leads to fewer neurons

24 Asymmetric distribution of cytoplasmic factors coordinated with orientation of mitotic spindle

25 Aspm protein localises to centrosomes

26 Knockdown of Aspm function leads to asymmetric division

27 Knockdown of Aspm results in more asymmetric divisions at early stages Effect is more progeny adopt neuronal fate and fewer retain neuroepithelial progenitor fate

28 Mutation of Aspm (or other genes implicated in microcephaly) causes: 1.Defect in alignment of mitotic spindle with axis of cell 2.Increase in asymmetric division at early stages 3.Failure to expand progenitor pool 4.Premature generation of neurons 5.Reduction in brain size

29 Conclusions:  Microcephaly caused by mutations in many genes  All involved in mitosis somehow  Defects in Aspm affect symmetric division  Progenitor pool fails to expand - depleted too early  Small brain results  ASPM, MCPH1, CDK5RAP2 all show evidence of positive selection in lineage leading to humans  Inference: Mutations in these genes that increased brain size may have been selected for in human lineage

30 Diversity of cell types and functions Red blood cells Hair cells in cochlea Skin cells Nerve cells Cardiac muscle cells

31 What makes cells different is they make different proteins Some proteins made only in specific cell types: e.g., hemoglobin, insulin

32 - Express different genes related to their specific functions (neurotransmitter receptors, ion channels, etc.) - Express specific code of transcription factors that control expression of all the other genes that make each cell unique (i.e. that specify its “identity”) - How do they come to express that spectrum of transcription factors? Each tissue/cell type has a different profile

33 Process of reiterative subdivision of embryo and progressive restriction of potential. - specification of intermediate fates of dividing cells en route to specification of final fates of postmitotic cells Occurs through series of cellular interactions beginning at the first cell division and continuing throughout development as morphogenetic movements shape embryo.

34 Gastrulation and Neural Induction

35 Patterning and establishment of cell fates 1. Gradients of diffusible molecules specify different fates at different concentrations 2. Interactions between neighbouring cells also influence cell fates

36 Different neuronal types generated from specific progenitor pools

37 Progenitor pools are specified by code of transcription factors (Briscoe et al., 2000)

38 Sharp borders between domains

39 Floor plate of spinal cord can induce ectopic motorneurons Wild-type situation Floor plate ablated Floor plate grafted motoneurons Floor plate (Embryological experiments in chick)

40 Shh conc. Sonic hedgehog is a secreted protein expressed in floor plate

41 Gradient of Shh induces different fates

42 Gradient of Shh induces some genes and represses others

43 How do you get such sharp borders? Cross-repression between transcription factors:

44 Cross-repression:  Nkx2.2 activates its own transcription and represses Pax6  Pax6 activates its own transcription and represses Nkx2.2  Both genes can’t be expressed in same cell - slight imbalance amplified - graded expression becomes sharp - individual cells specified as one fate or another

45 Combinatorial code of transcription factors  Control expression of other genes (i.e., turn on whole “profile” of gene expression for different subtypes of neurons)  These downstream “effector” genes control various aspects of cell fate: - Connectivity - Neurotransmitter expression - Expression of ion channels/receptors, etc.

46 Shh also patterns midline of brain and face

47 Mutations in Shh lead to Holoprosencephaly (OMIM: )

48 Midbrain dopaminergic neurons degenerate in Parkinson’s disease Specification of clinically important cell types

49 Parkinson’s disease Primary symptoms:  Tremor: an uncontrollable trembling or shaking  Rigidity: an abnormal stiffness of the muscles  Bradykinesia: an extreme slowness of movement and reflexes. Caused by progressive loss of midbrain dopaminergic neurons - can be familial (often early-onset) Current therapies (L-dopa) only moderately effective

50 Midbrain dopamine neurons induced by Shh and Fgf8 Shh Fgf8

51 Induction of midbrain dopaminergic neurons (side view) (dorsal view) Explants of neural tube in vitro: d2 v2 d3 v3 TH+ve neurons arise only in v3 in vivo and in explants in vitro

52 Add FP (source of Shh) to d3: dopaminergic neurons (TH +ve): Add isthmus (source of Fgf8) to v2: dopaminergic neurons (TH +ve): Block Shh function in v3 explant with antibody: no dopaminergic neurons (TH -ve):

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54 Inducing dopaminergic neurons from stem cells in vitro

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56 Summary Development of the nervous system involves many distinct processes in two main phases: - establishment of cell identities (patterning, proliferation, neurogenesis) - wiring (migration, axonal extension, synaptogenesis) Defects (due to genetic or environmental causes) in any of these processes can lead to specific clinical disorders Knowledge of developmental mechanisms can inform efforts to promote regeneration or stem cell replacement therapies

57 Transcription factors induced or repressed by Shh in concentration-dependent fashion Explants of medial spinal cord plus increasing concentrations of Shh

58 Diffusible Shh bound by transmembrane receptor proteins that transduce a signal intracellularly, eventually leading to activation of transcription factors. - At different concentrations this has different effects (it is a morphogen)

59 High affinity and low affinity binding sites Nkx2.2 Nkx6.1 Gli Low affinity sites: Gli binds weakly, not effective at low concentrations => Nkx2.2 only expressed very near floor plate ([Shh] high) High affinity sites: Gli binds strongly, effective even at low concentrations => Nkx6.1 expressed further away from floor plate (where [Shh] lower)


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