Hedgehog signaling is required for pituitary gland development

Pituitary gland development serves as an excellent model system in which to study the emergence of distinct cell types from a common primordium in mam malian organogenesis, We have investigated the role of the morphogen Sonic hedgehog (SHH) in outgrowth and differentiation of the pituitary gland usin g loss- and gain-of-function studies in transgenic mice. Shh is expressed t hroughout the ventral diencephalon and the oral ectoderm, but its expressio n is subsequently absent from the nascent Rathke's pouch as soon as it beco mes morphologically visible, creating a Shh boundary within the oral epithe lium, We used oral ectoderm/Rathke's pouch-specific 5' regulatory sequences (pitx1(HS)) from the bicoid related pituitary homeobox gene (Pitx1) to tar get overexpression of the Hedgehog inhibitor Hip (Hedgehog interacting prot ein) to block Hedgehog signaling, finding that SHH is required for prolifer ation of the pituitary gland. In addition, we provide evidence that Hedgeho g signaling, acting at the Shh boundary within the oral ectoderm, may exert a role in differentiation of ventral cell types (gonadotropes and thyrotro pes) by inducing Bmp2 expression in Rathke's pouch, which subsequently regu lates expression of ventral transcription factors, particularly Gata2, Furt hermore, our data suggest that Hedgehog signaling, together with FGF8/10 si gnaling, synergizes to regulate expression of the LIM homeobox gene Lhx3, w hich has been proved to be essential for initial pituitary gland formation. Thus, SHH appears to exert effects on both proliferation and cell-type det ermination in pituitary gland development.