SOX9-COL9A3-dependent regulation of choroid plexus epithelial polarity governs blood-cerebrospinal fluid barrier integrity.

The choroid plexus (CP) is an extensively vascularized neuroepithelial tissue that projects into the brain ventricles. The restriction of transepithelial transport across the CP establishes the blood-cerebrospinal fluid (CSF) barrier that is fundamental to the homeostatic regulation of the central nervous system microenvironment. However, the molecular mechanisms that control this process remain elusive. Here we show that the genetic ablation of Sox9 in the hindbrain CP results in a hyperpermeable blood-CSF barrier that ultimately upsets the CSF electrolyte balance and alters CSF protein composition. Mechanistically, SOX9 is required for the transcriptional up-regulation of Col9a3 in the CP epithelium. The reduction of Col9a3 expression dramatically recapitulates the blood-CSF barrier defects of Sox9 mutants. Loss of collagen IX severely disrupts the structural integrity of the epithelial basement membrane in the CP, leading to progressive loss of extracellular matrix components. Consequently, this perturbs the polarized microtubule dynamics required for correct orientation of apicobasal polarity and thereby impedes tight junction assembly in the CP epithelium. Our findings reveal a pivotal cascade of SOX9-dependent molecular events that is critical for construction of the blood-CSF barrier.

BMP/Smad signaling and embryonic cerebellum development: stem cell specification and heterogeneity of anterior rhombic lip.

The canonical bone morphogenetic proteins (BMPs) signaling have been shown to mediate many embryonic developmental processes. Due to its complexity, there are still many unknowns about this signal pathway including the Smad usage and requirement. Cerebellum, one of the most studied neural organs in development biology, requires canonical BMP signaling for stem cell specification. Here we review the role of canonical BMP signaling during the embryonic cerebellum development. Also, we raise several unsolved issues concerning the BMP signaling including the co-Smad independency of this signaling pathway. Besides, we also propose two models for explaining the cerebellar anterior rhombic lip (ARL) specification mechanisms. In addition, we review the heterogeneity of the ARL stem cells, which may provide new insight into understanding the neural stem cell specification process of the embryonic cerebellum.

Spatiotemporal Decline of BMP Signaling Activity in Neural Progenitors Mediates Fate Transition and Safeguards Neurogenesis.

Neural progenitors undergo temporal fate transition to generate diversified neurons in stereotyped sequence during development. However, the molecular machineries driving progenitor fate change remain unclear. Here, using the cerebellum as a platform, we demonstrate that the temporal dynamics of a dorsoventral bone morphogenetic protein (BMP)/SMAD signaling gradient orchestrates the transition from early to late phase of neurogenesis. Initially, high BMP/SMAD activity in cerebellum neural progenitors transcriptionally represses the late-born interneuron fate determinant Gsx1. As development proceeds, gradual decline in SMAD activities from ventral to dorsal progenitors progressively alleviates suppression on Gsx1 and allows transition of progenitor fate. Manipulating the BMP signaling dynamics can either lead to an immediate halt or rapid acceleration of the temporal fate switch, thus unbalancing the generation of distinct neuronal populations. Our study thus demonstrates that neural progenitors possess inherent competence to produce late-born neurons, yet identity transition is mechanistically executed by precisely timed and positioned reduction of repressors for late-fate determinants.