Multistep signaling requirements for pituitary organogenesis in vivo

Abstract

During development of the mammalian pituitary gland specific hormone-producing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordium. We have investigated the molecular basis of generating diverse pituitary cell phenotypes from a common precursor, providing in vivo and in vitro evidence that their development involves three sequential phases of signaling events and the action of a gradient at an ectodermal boundary. In the first phase, the BMP4 signal from the ventral diencephalon, expressing BMP4, Wnt5a, and FGF8, represents a critical dorsal neuroepithelial signal for pituitary organ commitment in vivo. Subsequently, a BMP2 signal emanates from a ventral pituitary organizing center that forms at the boundary of a region of oral ectoderm in which Shh expression is selectively excluded. This BMP2 signal together with a dorsal FGF8 signal, appears to create opposing activity gradients that are suggested to generate overlapping patterns of specific transcription factors underlying cell lineage specification events, whereas Wnt4 is needed for the expansion of ventral pituitary cell phenotypes. In the third phase, temporally specific loss of the BMP2 signal is required to allow terminal differentiation. The consequence of these sequential organ and cellular determination events is that each of the hormone-producing pituitary cell types-gonadotropes, thyrotropes, somatotropes, lactotropes, corticotropes, and melanotropes-appear to be determined, in a ventral-to-dorsal gradient, respectively.

How to make a teleost adenohypophysis: Molecular pathways of pituitary development in zebrafish

“…In addition, there is some, although less striking dorso-ventral polarity of the zebrafish adenohypophysis. For instance, gonadotropes are preferentially located ventral of thryrotropes and somatotropes M a n u s c r i p t 7 of the posterior PD (Glasgow et al, 1997, Nica et al, 2004, consistent with the ventral location of gonadotropes in Rathke's pouch, the AH anlage of the mouse ( (Treier et al, 1998, Zhu et al, 2005, Zhu et al, 2007. While the arrangement of PD in anterior and PI in posterior regions of the AH is conserved between zebrafish and mouse, the mouse PD per se does not display an apparent intrinsic anterior-posterior, but rather a dorso-ventral polarity (Treier et al, 1998, Zhu et al, 2005.…”

“…In mouse pituitary organogenesis, Shh secreted by the oral ectoderm and ventral cells of Rathke's pouch itself acts as a morphogen on the pouch where it promotes the differentiation of ventral cell fates and positively controls proliferation of pituitary precursors (Treier et al, 1998, Treier et al, 2001. A recent study by Guner and colleagues showed that Hh patterns the early zebrafish pituitary placode along its anterior-posterior axis, with highest signaling levels promoting anterior fates .…”

“…Shh, described above, acts together with Bone morphogenetic protein 2 (Bmp2) as a ventralizing factor, while Fgf8 secreted by the overlying ventral diencephalon promotes the specification of dorsal cell fates (Treier et al, 1998 , Liu et al, 2008.…”

FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription

“…Consistent with the BPES phenotype, FoxL2 is expressed in ovarian follicles and the developing eyelid (53). FoxL2 (initially named PFrk) is also present in the developing pituitary around e10 -10.5 (55). Moreover, FoxL2 expression persists in the adult pituitary and localizes mostly to cells positive for the glycoprotein ␣ subunit (␣GSU) shared by LH, FSH, and thyroid-stimulating hormone (TSH) (56).…”

Expression of GATA-2 in Human Pituitary Adenomas

“…It has been demonstrated that direct contact of the ventral diencephalons with Rathke's pouch is required for pituitary organogenesis and that pituitary cell type determination occurs in response to a series of extrinsic and intrinsic signaling molecules (2)(3)(4).…”