Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for formation of the neurohypophysis

Abstract

SUMMARYTbx2 and Tbx3 are two highly related members of the T-box transcription factor gene family that regulate patterning and differentiation of a number of tissue rudiments in the mouse. Both genes are partially co-expressed in the ventral diencephalon and the infundibulum; however, a functional requirement in murine pituitary development has not been reported. Here, we show by genetic lineage tracing that Tbx2 + cells constitute the precursor population of the neurohypophysis. However, Tbx2 is dispensable for neurohypophysis development as revealed by normal formation of this organ in Tbx2-deficient mice. By contrast, loss of Tbx3 from the ventral diencephalon results in a failure to establish the Tbx2 + domain in this region, and a lack of evagination of the infundibulum and formation of the neurohypophysis. Rathke's pouch is severely hypoplastic, exhibits defects in dorsoventral patterning, and degenerates after E12.5. In Tbx3-deficient embryos, the ventral diencephalon is hyperproliferative and displays an abnormal cellular architecture, probably resulting from a failure to repress transcription of Shh. We further show that Tbx3 and Tbx2 repress Shh by sequestering the SRY box-containing transcription factor Sox2 away from a Shh forebrain enhancer (SBE2), thus preventing its activation. These data suggest that Tbx3 is required in the ventral diencephalon to establish a Shh -domain to allow formation of the infundibulum.

Development of the hypothalamus: conservation, modification and innovation

“…Additional work has identified upstream regulators of Shh during hypothalamic patterning. In mice, Sox2 and Sox3 directly activate Shh in the rostral hypothalamus through the SBE2 enhancer, whereas Tbx2 and Tbx3 repress Shh in the caudal hypothalamus by sequestering Sox2 away from SBE2 (Trowe et al, 2013;Zhao et al, 2012). A similar pathway was shown in chick, where Bmp2 and Bmp7 activate Tbx2, which represses Shh expression in the caudal hypothalamus (Manning et al, 2006).…”

Sonic hedgehog in vertebrate neural tube development

“…Explant culture studies show that Fgf signals in an autocrine manner to promote proliferation of hypothalamic progenitors (Pearson et al, 2011). Studies in mice extended this work, showing that Tbx2 and Tbx3 repress Shh by sequestering Sox2 away from a Shh cis-regulatory element (Trowe et al, 2013), again, highlighting the importance of SoxB1 genes as activators of neural expression and their intimate association with Shh in the neural tube.…”

MAPK pathway activation in the embryonic pituitary results in stem cell compartment expansion, differentiation defects and provides insights into the pathogenesis of papillary craniopharyngioma

“…Histological processing of embryos and in situ hybridisation on paraffin sections was performed as previously described Sajedi et al, 2008). The antisense riboprobes used in this study (Fgf10, Shh, Bmp4 and Lhx3) have been described Sajedi et al, 2008;Jayakody et al, 2012;Trowe et al, 2013). Full-length Braf and Kras antisense riboprobes were obtained from Source Bioscience (PX00999A07 and IRAVp968D072D, respectively).…”