During corticogenesis, early-born neurons of the preplate and layer 6 are important for guiding subsequent neuronal migrations and axonal projections. Tbr1 is a putative transcription factor that is highly expressed in glutamatergic early-born cortical neurons. In Tbr1-deficient mice, these early-born neurons had molecular and functional defects. Cajal-Retzius cells expressed decreased levels of Reelin, resulting in a reeler-like cortical migration disorder. Impaired subplate differentiation was associated with ectopic projection of thalamocortical fibers into the basal telencephalon. Layer 6 defects contributed to errors in the thalamocortical, corticothalamic, and callosal projections. These results show that Tbr1 is a common genetic determinant for the differentiation of early-born glutamatergic neocortical neurons and provide insights into the functions of these neurons as regulators of cortical development.

The large extracellular matrix protein Reelin is produced by Cajal-Retzius neurons in specific regions of the developing brain, where it controls neuronal migration and positioning. Genetic evidence suggests that interpretation of the Reelin signal by migrating neurons involves two neuronal cell surface proteins, the very low density lipoprotein receptor (VLDLR) and the apoE receptor 2 (ApoER2) as well as a cytosolic adaptor protein, Disabled-1 (Dab1). We show that Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro and that blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons. Furthermore, mice that lack either Reelin or both VLDLR and ApoER2 exhibit hyperphosphorylation of the microtubule-stabilizing protein tau. Taken together, these findings suggest that Reelin acts via VLDLR and ApoER2 to regulate Disabled-1 tyrosine phosphorylation and microtubule function in neurons.

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Cilia are organelles that protrude from the apical surface of most eukaryotic cells. According to their structure and motility, they are classified into three groups 1 . Primary monocilia, present in most cells, lack a central pair of microtubules (9+0 structure), and play several roles in mechanosensation and cell signaling. Nodal cilia have a 9+0 structure but, unlike primary cilia, they move and generate an asymmetric distribution of morphogenetic cues in the node, thereby contributing to laterality 2 . The third group is composed of motile 9+2 cilia that cover epithelial cells lining airways, reproductive tracts, and cerebral ventricles. Motile cilia play crucial functions in clearing mucus and debris in the airways and may assist the transit of sperm and eggs in genital tracts [3][4] . In the early postnatal mammalian brain, neuroepithelial cells that line the cerebral ventricles leave the cell cycle and differentiate into a monolayer of ependymal cells. At the end of maturation, the apical surface of ependymal cells bears dozens of cilia that beat in coordinate manner to facilitate the circulation of the cerebrospinal fluid (CSF), from sites of production in choroid plexuses to sites of absorption in subarachnoid spaces. In mice, mutations in genes involved in the assembly or structure of ependymal cilia, such as Mdnah5 5 , Ift88 (also known as Tg737 or Polaris) 6 , and Hy3 7-8 affect cilia genesis, CSF dynamics, and result in hydrocephalus. Thus far, however, little is known about the genetic factors that govern ependymal cilia polarization and the relationship between the polarity and the development and function of these organelles.Planar cell polarity (PCP), also known as tissue polarity, controls the polarization of epithelial cells in a plane perpendicular to their apicobasal axis. It was initially described in Drosophila, where it affects the stereotypic arrangement of cuticular hairs, sensory bristles, and Supplementary Fig. 1a, b). RT-PCR and (Supplementary Fig. 1c).Using the knocked-in beta-galactosidase reporter, we monitored the expression of Celsr2 in heterozygous mice. Consistent with published data [24][25][26] , Celsr2 expression was detected in all brain areas, from E11.5 to P5 (Fig. 1a-h). Celsr2 mutant mice develop progressive hydrocephalusCelsr2 mutant mice were viable and fertile, except for some females that had vaginal atresia. At birth, their brain did not display any flagrant morphological abnormality, suggesting that Celsr2 is not critical for cerebral embryonic development. However, a progressive ventricular dilation appeared between P5 and P10 with variable severity between animals, and became evident at P21 (Fig. 2a,b).The lateral ventricles were enlarged, and the septum had an abnormal triangular shape, due to 6 6 reduction of the dorsal part of the lateral septum. We did not observe any stenosis or constriction at the level of the foramen of Monro or of the aqueduct. The subcommissural organ (SCO), a structure thought to play a role in non-communicating hydrocephalus, was...

The cerebral cortex of mice with a targeted disruption in the gene for cyclin-dependent kinase 5 (cdk5) is abnormal in its structure. Bromodeoxyuridine labeling reveals that the normal inside-out neurogenic gradient is inverted in the mutants; earlier born neurons are most often found superficial to those born later. Despite this, the early preplate layer separates correctly and neurons with a normal, pyramidal morphology can be found between true marginal zone and subplate. Consistent with their identity as layer VI corticothalamic neurons, they can be labeled by DiI injections into thalamus. The DiI injections also reveal that the trajectories of the cdk5 Ϫ/Ϫ thalamocortical axons are oblique and cut across the entire cortical plate, instead of being oriented tangentially in the subcortical white matter. We propose a model in which the cdk5 Ϫ/Ϫ defect blocks cortical development at a heretofore undescribed intermediate stage, after the splitting of the preplate, but before the migration of the full complement of cortical neurons.