However, the role of Shh signaling during early embryonic CNS development is largely confined to the ventral regions. In the central nervous system (CNS), Shh is well recognized for its role in patterning different ventral neuronal cell types during early embryogenesis and in promoting cerebellar granule precursor cell proliferation( Goodrich et al., 1997 Wallace, 1999 Dahmane and Ruiz i Altaba,1999 Wechsler-Reya and Scott,1999). However, continued growth of the hChP beyond E14 suggests contribution by other hChPe progenitor sources besides early contribution by the hRPe and anterior LRL. A recent study indicates that Wnt1-expressing LRL cells can directly contribute to hChPe from E10 to E14 but this contribution ceases around E14 ( Hunter and Dymecki,2007).
Genetic fate-mapping studies have shown that hChPe cells are derived from progenitor cells residing in the anterior lower rhombic lip(LRL), which is positioned between the developing hChP and medulla, with the expression of secreted growth factors Wnt1, Gdf7 and LIM-domain transcription factor Lmx1a ( Awatramani et al.,2003 Chizhikov et al.,2006 Currle et al.,2005). Previous studies suggest that the rhombic lip, a germinal zone, first gives rise to the hindbrain roof plate epithelium (hRPe), which is further specified, potentially by high levels of Bmp signaling( Hebert et al., 2002), into definitive hChPe ( Thomas and Dziadek,1993). The hChP epithelium (hChPe)initially emerges as a single sheet of pseudostratified cells, but by E13.5 the hChPe adopts a simple columnar morphology with numerous microvilli at the surface ( Sturrock, 1979). hChP consists of an outer epithelial layer and an inner core of stromal cells that are surrounded by a dense vascular network.
Outgrowth of the hChP is clearly evident at E12.5 as a pair of bilateral ridges protruding from the roof of the hindbrain, gradually developing into a highly convoluted organ with extensive epithelial folding. Among all ChPs, hChP emerges earliest during embryogenesis and is conspicuously large. ChPs originate from four focal sites at the roof of the brain ventricles: two in the lateral ventricles of the telencephalon, one in the third ventricle of the diencephalon and one in the fourth ventricle of the hindbrain (hChP). The ChP epithelium has been the focus of extensive studies, as it serves as the blood-CSF barrier( Redzic et al., 2005 Segal, 2000). 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.Ĭhoroid plexuses (ChPs) are heavily vascularized secretory organs in the brain, which serve as sites of cerebrospinal fluid (CSF) production and are also known to generate chemicals and polypeptides with neuroprotective,surveillance and repair functions. 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. 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. However, we identify a distinct epithelial domain in the hChP that does not express Shh,but displays Shh signaling. Sonic hedgehog (Shh), a secreted signal crucial for embryonic development and cancer, is strongly expressed in the differentiated hindbrain ChP epithelium (hChPe). Despite their crucial roles, there is limited understanding of the regulatory mechanism driving ChP development. Choroid plexuses (ChPs) are vascularized secretory organs involved in the regulation of brain homeostasis, and function as the blood-cerebrospinal fluid(CSF) barrier.
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