Neuronal migration


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Neuronal migration

  1. 1. Adapted from: Li-Huei Tsai Joseph G. GleesonCatherine Lambert de Rouvroit Andre G. Goufinet
  2. 2. During development neurons migrate from the subventriculararea of the brain to the surface of the brain under theinfluence of glia produced -chemoattractants or -chemorepellents During embriogenesis neurons migrate approximately 2 cm(hundreds of cell body distances) to their final destination.
  3. 3.  Many human neurologic diseases are directly or indirectly linked to disordered neuronal migration. Many genes that have been found to play critical roles in neuronal migration during development also appear to be central to the pathogenesis of neurodegenerative disorders in the adult. In epilepsy and schizophrenia there is evidence that disordered neuronal migration may contribute to the pathogenesis, as one of the more frequent findings in these conditions is heterotopically located neurons in various positions of the CNS.
  4. 4.  Neuronal migration occurs in three stages:1. Leading Edge Extension2. Nuclear Translocation (Nucleokinesis)3. Retraction of Trailing Process
  5. 5. Leading edge extension is directed by actin polymerization (directedby attractive or repulsive extracellular cues). It is regulated by Rhotype small GTPases.In humans, mutations of filamin (an actin-associated protein), resultin heterotopic neurons, probably due to defective leading edgeextension.
  6. 6.  Nuclear translocation is composed of two sub-phases:-Centrosome Positioning-Movement of the nucleus towards the centrosome As the neuron migrates there are major cytoskeletal alterations in the actin and microtubule (MT) cytoskeletons. Microtubules appear to emanate from a single location (centrosome) just in front of the nucleus and to extend anteriorly into the leading process and posteriorly to envelop the nucleus.
  7. 7. Lis1 and nucleocortin proteins interact with the microtubules.Dynein is a microtubular molecular motor composed of 2proteins: Nudel1 and NudE.Lis1 protein interacts with dynein (Nudel1 and NudE ) proteins.Defects in dynein activity lead to alterations in nuclear-centrosome coupling.
  8. 8.  In humans, mutations in the LIS1 or doublecortin (DCX) gene result in type 1 lissencephalies (which literally means smooth brain) caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in a lack of development of brain folds and grooves.
  9. 9.  The end of migration requires the integrity of the Reelin signalling pathway. Reelin is thought to trigger recognition-adhesion among target neurons. Other known components of the retraction of the trailing process include members of the lipoprotein receptor family Dab1, and possibly integrin alpha 3 beta 1. Deffects of the external limiting membrane lead to overmigration of neurons in meninges (type 2 lissencephaly).