Multistep signaling requirements for pituitary organogenesis in vivo

  1. Mathias Treier1,
  2. Anatoli S. Gleiberman1,2,5,
  3. Shawn M. O’Connell1,5,
  4. Daniel P. Szeto1,3,
  5. Jill A. McMahon4,
  6. Andrew P. McMahon4, and
  7. Michael G. Rosenfeld1,6
  1. 1Howard Hughes Medical Institute, 2Eukaryotic Regulatory Biology Program, 3Biomedical Sciences Graduate Program, University of California, San Diego, School and Department of Medicine, La Jolla, California 92093-0648 USA; 4The Biolabs, Harvard University, Cambridge, Massachusetts 02138 USA

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, andFGF8, 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.

Keywords

Footnotes

  • 5 These authors contributed equally to this work.

  • 6 Corresponding author.

  • E-MAIL mrosenfeld{at}ucsd.edu; FAX (619) 534-8180.

    • Received March 23, 1998.
    • Accepted April 21, 1998.
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