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Cell migration in the cerebral cortex How does it work? What happens when it goes wrong? Story of interplay between basic and clinical science.

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Presentation on theme: "Cell migration in the cerebral cortex How does it work? What happens when it goes wrong? Story of interplay between basic and clinical science."— Presentation transcript:

1 Cell migration in the cerebral cortex How does it work? What happens when it goes wrong? Story of interplay between basic and clinical science

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3 Inside-out programme of neurogenesis

4 Somal translocationGlial-guided locomotion

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6 “Reeler” mutant mice - Mice are ataxic, fall over a lot - Lack cerebellum - Layers in cerebral cortex are inverted

7 Inverted cortical layers in reeler mutants

8 “Reeler” mutation mapped to gene, named Reelin. - Encodes large secreted protein - Specifically expressed by Cajal-Retzius cells in marginal zone of developing cortex - Mutations in the human Reelin gene result in Lissencephaly with Cerebellar Hypoplasia

9 (OMIM: ) - Autosomal recessive - Simplified folding of cortex (“smooth” cortex) - Cerebellum very underdeveloped - Severe ataxia, mental retardation and epilepsy

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11 “Scrambler” mutant mice show same behavioural and anatomical defects as Reeler mice - Mapped to gene Dab1 - Encodes cytoplasmic “adaptor” protein - Link cytoplasmic tails of transmembrane proteins to intracellular signaling proteins => Maybe in same biochemical pathway as Reelin? What’s in between them?

12 ? Reelin (secreted from MZ cells) Dab1 Outside Inside (inside migrating neuron)

13 Dab1 protein found to bind to cytoplasmic tails of two transmembrane proteins (related to each other): - VLDLR and ApoER2 (very low density lipoprotein receptor and ApoE receptor 2) - These proteins found to bind Reelin through their extracellular domains - Binding of Reelin leads to phosphorylation of Dab1 protein

14 VLDLR Reelin (secreted from MZ cells) Dab1 Outside Inside (inside migrating neuron) ApoER2 P

15 What happens when these genes are mutated? - Knock out VLDLR in mice: very little effect - Knock out ApoER2 in mice: very little effect - Make double KO: looks just like reeler mutants => These proteins are redundant in this process

16 Upon Reelin binding to VLDLR or ApoER2: - Dab1 recruited - Dab1 phosphorylated by Src or Fyn (Src;Fyn double mutant has same phenotype as Dab1) - Signaling to cytoskeleton - Phosphorylated Dab1 degraded (entire complex including receptors endocytosed and degraded)

17 VLDLR Reelin (secreted from MZ cells) Dab1 Outside Inside (inside migrating neuron) ApoER2 P Src/Fyn

18 But what is the process at a cellular level? - Ultimate defect is inverted layers but what causes that? - What cellular effects does Reelin have? - Not a chemoattractant - Not a “stop signal”

19 Reelin protein shown to stimulate detachment of migrating neurons in vitro - in this case it was cells migrating to the olfactory bulb but concept same - Dab signaling shown to: (i) reduce expression of adhesion molecules (  3-integrin) (ii) promote detachment from radial glia

20 GFP transfection can label radial units (glia and neurons)

21 Migrating neurons fail to detach from radial glia wild-typedab1 mutants

22 But what is the process at a cellular level? - Failure to detach from radial glia - Creates “logjam”; newly generated neurons can’t get past first ones  Layers form in outside-in order, instead of inside-out order

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25 Other types of cortical defects: - Classical lissencephaly - Double cortex syndrome

26 Classical Lissencephaly (OMIM: ) - Autosomal dominant - Very little folding of cortex (“smooth” cortex) - Four primitive layers instead of six - Cerebellum normal - Mental retardation, microcephaly and epilepsy Caused by mutations in LIS1 gene

27 Double cortex syndrome (OMIM: ) - X-linked dominant - Cortex completely smooth and highly thickened - Four primitive layers instead of six - Severe mental retardation and epilepsy in males - Milder symptoms in heterozygous females Caused by mutations in DCX gene

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30 Staining for DCX protein highlights microtubulues

31 LIS1 and DCX proteins both bind to microtubules (part of cytoskeleton that controls migration) - Required early for somal translocation (within cell’s own process) as well as later for migration along glia - Both interact with microtubules in dynamic fashion - LIS1 also interacts with VLDLR and binds phsophorylated Dab1 in response to Reelin signaling  link from Dab1 to cytoskeleton

32 Actin filament- interacting proteins Microtubule- interacting proteins DCX

33  Prenatal/neonatal risk factors  Early prodromal signs  Distributed neuropathology - local and long-range  Genes implicated - Nrg1, DISC1, DTNBP1 - have roles in neurodevelopment Schizophrenia as a neurodevelopmental disorder

34 Summary of observed pathological changes (Frankle, 2003)

35 Cell migration defects in schizophrenia? DISC1 - Broken by translocation in certain families with SZ - Protein binds NUDEL (which binds LIS1) - Truncated protein does not bind - Truncated form reduces neurite outgrowth when transfected into PC12 cells

36 Mutations in DISC1 are associated with schizophrenia and other psychiatric disorders

37 Mice with mutations in DISC1 show behavioral defects thought to be “endophenotypes” of schizophrenia: - hyperactivity - prepulse inhibition (suppression of startle response) - working memory Disrupting DISC1 function ONLY during development still results in behavioural defects => Neurodevelopmental functions of DISC1 essential for normal brain structure and function

38 Tangential migration also very important - Especially for GABAergic (inhibitory) interneurons - Not generated in cortical ventricular zone - Generated subcortically in ganglionic eminences - Migrate long distance to cortex - Controlled by positive and negative guidance cues

39 Interneurons generated subcortically and migrate to cortex

40 (Flames et al., 2004, Neuron 44, 251) Neuregulin-1 in control of radial migration

41 Nrg1 protein attracts interneurons to cortex Slice of developing mouse brain - interneurons (red) normally migrate up to cortex but will be attracted to cells expressing Nrg1 protein placed on slice (green)

42 Mutant mice lacking Nrg1 in cortex have fewer interneurons in cortex

43  ErbB4 is receptor for secreted Nrg1 protein  Nrg1 and ErbB4 both genetically associated with SZ in humans  Nrg1 and ErbB4 mutants lethal in mice  But heterozygotes live and show hyperactivity and other “endophenotypes” of schizophrenia - e.g., working memory deficits  Reversed by clozapine (no effect on wild-type activity) Neuregulin-1 and ErbB4 in schizophrenia

44 Summary - Cell migration is a complex process that is crucial for nervous system development in general and cortical function in particular - Severe clinical syndromes caused by mutations in a number of single genes - More subtle genetic variation in cell migration genes may contribute to multigenic disorders such as epilepsy, schizophrenia and autism. (Caveat: genes like DISC1 and Nrg1 also have non- developmental roles in adult)

45 References: Olson and Walsh (2002) Curr. Opin. Genetics and Development 12, 320 Marin and Rubenstein (2001) Nat. Rev. Neurosci. 2, 780 Websites with nice movies:

46  3-integrin not downregulated in scrambler mice

47  ntegrins bind extracellular matrix molecules and mediate cell adhesion

48 Blocking  3-integrin in scm cortical slice restores normal detachment

49 Several types of defects observed:

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