Martins da Costa, Maria Cristina; (2000) Genetic and developmental studies of neuronal migration defects in the mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The dreher mutation is inherited as an autosomal recessive trait. Homozygotes are deaf, have an abnormal inner ear, display circling behaviour and have white belly spots. They also have misplaced neurons (heterotopia) in the central nervous system, involving both the cerebral hemispheres and the cerebellum. The main goals of this thesis were to accurately map the dreher gene, in order to develop a reliable way of genotyping each mouse, to assess candidate genes in the dreher region, and to elucidate the mechanisms underlying neuronal migration defects in drJ homozygous mutant mice. Using microsatellite DNA markers to genotype the progeny from known heterozygotes, recombinant animals have been identified on the basis of PCR polymorphism analysis. This has enabled the repositioning of the dreher gene to a 5.22 cM interval on distal mouse Chromosome 1, proximally to its previously assigned location. Two genes mapping to the critical region, astrotactin and Pou2f1, were evaluated as candidates for dreher. Expression analysis and limited gene sequencing failed to disclose consistent differences in either gene between drJ/drJ and wild type embryos. Studies of the survival of drJ/drJ mice in the prenatal period, and at various postnatal ages, indicate that there is increased mortality among homozygous mutants postnatally, probably as a result of starvation caused by the circling behaviour. In order to evaluate the possible mechanisms underlying the presence of heterotopic neurons in layer I of the neocortex, birthdating studies have been performed by labelling with bromodeoxyuridine. This analysis shows that the misplaced neurons are generated predominantly or exclusively during the late stages of neocortical histogenesis in drJ/drJ fetuses. A histopathological and immunohistochemical analysis of brains indicates that the glial limiting membrane overlying the areas of heterotopic neurons is disrupted. This abnormality is suggested to play a central role in the pathogenesis of misplaced neurons in drJ/drJ brains, by defective radial glial-guided neuronal migration.

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