Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus

Abstract

Choroid plexuses (ChPs) are vascularized secretory organs involved in the regulation of brain homeostasis, and function as the blood-cerebrospinal fluid(CSF) barrier. Despite their crucial roles, there is limited understanding of the regulatory mechanism driving ChP development. Sonic hedgehog (Shh), a secreted signal crucial for embryonic development and cancer, is strongly expressed in the differentiated hindbrain ChP epithelium (hChPe). However, we identify a distinct epithelial domain in the hChP that does not express Shh,but displays Shh signaling. We find that this distinct Shh target field that adjoins a germinal zone, the lower rhombic lip (LRL), functions as a progenitor domain by contributing directly to the hChPe. By conditional Shh mutant analysis, we show that Shh signaling regulates hChPe progenitor proliferation and hChPe expansion through late embryonic development, starting around E12.5. Whereas previous studies show that direct contribution to the hChPe by the LRL ceases around E14, our findings reveal a novel tissue-autonomous role for Shh production and signaling in driving the continual growth and expansion of the hindbrain choroid plexus throughout development.

Transventricular delivery of Sonic hedgehog is essential to cerebellar ventricular zone development

“…Notably, the hindbrain choroid plexus is in close apposition with the cerebellar VZ throughout development (Fig. 4), and it is the only choroid plexus that expresses Shh (13). The observation that the hindbrain medulla, the only other noncerebellar source of Shh within the developing hindbrain system, is not required for expansion of VZ progenitors supports the argument that the hChP contributes to cerebellar VZ development.…”

“…Shh signaling activity was not detectable in the cerebellum at E12.5, although evident in the developing hChP at all stages presented ( Fig. 1) (13). Because radial glial cells are localized to the apical surface of the brain ventricular zone and recognized as the major source of neural progenitors in the cerebellum (10), we examined whether Shh signaling is activated in these cells.…”

“…We have recently reported that the developing hindbrain choroid plexus epithelium (hChPe) robustly expresses Shh, which targets a discrete epithelial tissue situated between the hChP and lower RL (13). This distinct epithelial domain functions as the hChPe progenitor domain, which directly contributes to hChP epithelial growth by a proliferative process that depends on active Shh signaling activity (13).…”

“…We have recently reported that the developing hindbrain choroid plexus epithelium (hChPe) robustly expresses Shh, which targets a discrete epithelial tissue situated between the hChP and lower RL (13). This distinct epithelial domain functions as the hChPe progenitor domain, which directly contributes to hChP epithelial growth by a proliferative process that depends on active Shh signaling activity (13). To our surprise, during our examination of the expression of Gli1 and Ptch1 by RNA in situ hybridization for Shh pathway activation in the hChP and surrounding tissue, the adjacent cerebellum, we also detected Shh signaling pathway activity in the cerebellar VZ along the medial-lateral axis at E14.5 ( Fig.…”

Vive la science ! Vive le hérisson !

“…chin chiang (Vanderbilt u. ) demonstrated that Hh signalling also functions earlier in cerebellar development to promote the proliferation of ventricular zone radial glial cells (Huang et al, 2009). However, Shh is not expressed in the cerebellum during these early stages.…”