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

Abstract

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.”

Cellular and Axonal Constituents of Neocortical Molecular Layer Heterotopia

“…Second, there is evidence that the cellular constituents of heterotopia in mutant/KO mice are similar to those seen in MLH in C57BL/6J mice. For example, in the following mutant/KO mice: Fak [22], Gpr56 [15], Col3a1 [71], Dag1 [72] and Foxc1 [73], heterotopia were found to contain layer V neurons that express CTIP2 and/or ER81, which is similar to our findings in C57BL/6J mice. Moreover, heterotopia in Zic1/3 mutants [74] were found to contain GAD-expressing neurons similar to our observations.…”

220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27–29 May 2016

“…In the developing brain, dystroglycan is found on the basal endfeet of embryonic radial glia [16] and the loss of radial glial attachment to the pial basement membrane is thought to underlie neuronal migration defects in these dystroglycanopathies [17]. In the adult brain, dystroglycan is found on the LG domains, and is consistent with prior mutagenesis results of neurexin domains LG2 and LG6.…”

Dynamic mRNA Transport and Local Translation in Radial Glial Progenitors of the Developing Brain

“…The basal process is a scaffold for migrating excitatory neurons, and its asymmetric inheritance following cell division correlates with progenitor cell fate [3, 8]. Basal endfeet interactions with the overlying lamina define the pial border for migrating neurons [9, 10]. Extrinsic cues from the basal niche cells influence RGCs [4, 5, 11, 12], suggesting that endfeet also may promote signaling back to the cell body [13, 14].…”