POMT1-Associated Walker-Warburg Syndrome: A Disorder of Dendritic Development of Neocortical Neurons

Judaš, Miloš; Sedmak, Goran; Radoš, Marko; Sarnavka, Vladimir; Fumić, Ksenija; Willer, Tobias; Groß, Claudia; Hehr, Ute; Strahl, Sabine; Ćuk, Martin; Barić, Ivo

doi:10.1055/s-0029-1224099

Cited by 13 publications

(14 citation statements)

References 25 publications

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“…The development of appropriate cortical connections involves axon pathfinding mediated by extrinsic molecular signals in addition to reciprocal interactions with cortical afferent axons (70). Within the heterotopia of Dag1 cKO brains, some pyramidal neurons showed altered polarity including abnormally oriented or bent apical dendrites, closely resembling the morphology of neocortical neurons in humans with Walker-Warburg syndrome and cobblestone lissencephaly (76). Despite severe dyslamination and abnormal dendrite orientation, heterotopic pyramidal neurons established axonal connections with distant cortical and subcortical targets or projections within appropriate white matter tracts.…”

Section: Discussionmentioning

confidence: 71%

Dystroglycan on Radial Glia End Feet Is Required for Pial Basement Membrane Integrity and Columnar Organization of the Developing Cerebral Cortex

Myshrall

Moore

Ostendorf

et al. 2012

J Neuropathol Exp Neurol

121

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Interactions between the embryonic pial basement membrane (PBM) and radial glia (RG) are essential for morphogenesis of the cerebral cortex, as disrupted interactions cause cobblestone malformations. To elucidate the role of dystroglycan (DG) in PBM-RG interactions, we studied the expression of DG protein and Dag1 mRNA (which encodes DG protein) in developing cerebral cortex, and analyzed cortical phenotypes in Dag1 CNS conditional mutant mice. In normal embryonic cortex, Dag1 mRNA was expressed in the ventricular zone, which contains RG nuclei whereas DG protein was expressed at the cortical surface on RG endfeet. Breaches of PBM continuity appeared during early neurogenesis in Dag1 mutants. Diverse cellular elements streamed through the breaches to form leptomeningeal heterotopia that were confluent with the underlying residual cortical plate and contained variably truncated RG fibers, many types of cortical neurons, and radial and intermediate progenitor cells. Nevertheless, layer-specific molecular expression appeared normal in heterotopic neurons, and axons projected to appropriate targets. Dendrites, however, were excessively tortuous and lacked radial orientation. These findings indicate that DG is required on RG endfeet to maintain PBM integrity and suggest that cobblestone malformations involve disturbances of radial glia structure, progenitor distribution, and dendrite orientation in addition to neuronal “overmigration.”

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Section: Discussionmentioning

confidence: 71%

Dystroglycan on Radial Glia End Feet Is Required for Pial Basement Membrane Integrity and Columnar Organization of the Developing Cerebral Cortex

Myshrall

Moore

Ostendorf

et al. 2012

J Neuropathol Exp Neurol

121

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“…The 18 coding exons (exons 2-20) and intron-exon boundaries of the POMT1 gene were amplified by PCR. 5,14 PCR products were sequenced using the ABI Prism BigDye Terminator v1.1 Cycle Sequencing Kit and analyzed on an ABI 3100 Avant sequencer (Applied Biosystems).…”

Section: Cell Lines and Mutation Analyses Primary Dermal Fibro-mentioning

confidence: 99%

Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies

Lommel

Çırak²,

Willer³

et al. 2010

Neurology

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Our results suggest that dermal fibroblasts can be applied to facilitate the diagnostic analysis of dystroglycanopathy patients as well as to study the pathogenic mechanism of POMT mutations. Characterization of the POMT1 substrate protein alpha-dystroglycan and POMT in vitro mannosyltransferase activity shows that the severity of the clinical phenotype of the patients analyzed is inversely correlated with POMT activity.

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“…Alterations in dendritic tree morphology have been reported in human neurological diseases, in particular those associated with mental retardation. Studies using Golgi staining of post-mortem material from children with mental retardation-associated syndromes report defects in dendritic branching, indicating a need to uncover the molecular mechanisms that regulate this process (Marin-Padilla 1972;Huttenlocher 1974;Takashima et al 1989;Bauman et al 1995;Armstrong et al 1998;Schule et al 2008;Judas et al 2009). …”

mentioning

confidence: 99%

Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin

Rosário

Schuster²,

Jüttner³

et al. 2012

Genes Dev.

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Neocortical neurons have highly branched dendritic trees that are essential for their function. Indeed, defects in dendritic arborization are associated with human neurodevelopmental disorders. The molecular mechanisms regulating dendritic arbor complexity, however, are still poorly understood. Here, we uncover the molecular basis for the regulation of dendritic branching during cortical development. We show that during development, dendritic branching requires post-mitotic suppression of the RhoGTPase Cdc42. By generating genetically modified mice, we demonstrate that this is catalyzed in vivo by the novel Cdc42-GAP NOMA-GAP. Loss of NOMA-GAP leads to decreased neocortical volume, associated specifically with profound oversimplification of cortical dendritic arborization and hyperactivation of Cdc42. Remarkably, dendritic complexity and cortical thickness can be partially restored by genetic reduction of post-mitotic Cdc42 levels. Furthermore, we identify the actin regulator cofilin as a key regulator of dendritic complexity in vivo. Cofilin activation during late cortical development depends on NOMA-GAP expression and subsequent inhibition of Cdc42. Strikingly, in utero expression of active cofilin is sufficient to restore postnatal dendritic complexity in NOMA-GAP-deficient animals. Our findings define a novel cell-intrinsic mechanism to regulate dendritic branching and thus neuronal complexity in the cerebral cortex.

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POMT1-Associated Walker-Warburg Syndrome: A Disorder of Dendritic Development of Neocortical Neurons

Cited by 13 publications

References 25 publications

Dystroglycan on Radial Glia End Feet Is Required for Pial Basement Membrane Integrity and Columnar Organization of the Developing Cerebral Cortex

Dystroglycan on Radial Glia End Feet Is Required for Pial Basement Membrane Integrity and Columnar Organization of the Developing Cerebral Cortex

Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies

Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin

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