title: Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for formation of the neurohypophysis.
abstract: Tbx2 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.
authors.affiliation: Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
authors.forename: Mark-Oliver
authors.initials: MO
authors.lastname: Trowe
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.forename: Anna-Carina
authors.initials: AC
authors.lastname: Weiss
authors.forename: Vincent
authors.initials: V
authors.lastname: Christoffels
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Epstein
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004027:Diencephalon / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000196:embryology; D010904:Pituitary Gland, Posterior / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*; D013997:Time Factors
chemical_list: D053823:Hedgehog Proteins; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse
keywords: Diencephalon; Infundibulum; Neurohypophysis; Pituitary gland