Neural progenitor fate decision defects, cortical hypoplasia and behavioral impairment in Celsr1-deficient mice.

The development of the cerebral cortex is a tightly regulated process that relies on exquisitely coordinated actions of intrinsic and extrinsic cues. Here, we show that the communication between forebrain meninges and apical neural progenitor cells (aNPC) is essential to cortical development, and that the basal compartment of aNPC is key to this communication process. We found that Celsr1, a cadherin of the adhesion G protein coupled receptor family, controls branching of aNPC basal processes abutting the meninges and thereby regulates retinoic acid (RA)-dependent neurogenesis. Loss-of-function of Celsr1 results in a decreased number of endfeet, modifies RA-dependent transcriptional activity and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production. The mutant cortex has a reduced number of neurons, and Celsr1 mutant mice exhibit microcephaly and behavioral abnormalities. Our results uncover an important role for Celsr1 protein and for the basal compartment of neural progenitor cells in fate decision during the development of the cerebral cortex.

Reelin does not directly influence axonal growth.

Reelin is a large extracellular glycoprotein involved in the development of architectonic patterns, particularly in the cerebral cortex and hippocampus, where it is synthesized primarily by Cajal-Retzius cells. In the hippocampus, Reelin also regulates the growth and/or distribution of afferent entorhinal and commissural axons. To assess further the possible action of Reelin on axonal growth, we used the three-dimensional collagen gel assay to measure axonal elongation from reeler cortical explants in the presence of Reelin. Because Reelin is proteolytically processed in vivo, normal explants and Reelin-transfected human embryonic kidney 293T cells were used, respectively, as sources of processed and full-length protein. The reliability of the assay was tested by demonstrating a clear repulsive action of semaphorin 3F (p < 0.0001). However, neither full-length nor processed Reelin exhibited any significant attraction or repulsion on cortical axons. Our results suggest that the reported effects of Reelin on axonal pathways are indirect, secondary to the architectonic disturbances that result from Reelin deficiency, and that the effects of Cajal-Retzius cells on connectivity are primarily independent of Reelin.