Induction and patterning of the hypothalamus and pituitary: transcriptional control of signaling pathways

Abstract

The developing anterior pituitary provides an excellent model system for investigating cell differentiation events as the phenotype of the hormone secreting cells, and the critical morphogen gradients required for their emergence, are well defined. In the murine embryo, pituitary development begins at approximately 9.5 days post coitum (dpc) with the invagination of oral ectoderm at the anterior ventral midline to form Rathke's Pouch. From 9.5-13.5 dpc, transcription factor expression within the pituitary primordium becomes regionally restricted in response to FGF and BMP signals from neighbouring tissues including the hypothalamus and infundibulum. Genetic studies in mice and humans have shown that these transcription factors control the commitment and terminal differentiation of the five hormone-secreting lineages. However, little is currently known about the downstream targets of these factors. We have shown previously that the NOTCH2 receptor is specifically expressed in pituitary progenitor cells and is downstream of PROP1, a key pituitary transcription factor that is essential for differentiation of most hormone-secreting lineages. To investigate NOTCH2 function in pituitary development, we generated transgenic mice that express a constitutively active form of NOTCH2 in pituitary progenitor cells. These mice exhibited a delay in gonadotrope differentiation and altered expression of Notch signaling targets. These data provide the first direct evidence for a functional requirement of the Notch signaling pathway in pituitary organogenesis and suggest that Notch2 acts as an inhibitor of pituitary cell differentiation.