Download Molecular Involvement of the Pit-2 Gene in Anterior Pituitary Cell

Molecular Involvement of the Pit-2 Gene in
Anterior Pituitary Cell Commitment'
Simon J. Rhodes* and Michael G. Rosenfeld?
*Department of Biology, Indiana University-Purdue University
a t Indianapolis, Indianapolis, IN 46202-5132
and +Department of Medicine and Howard Hughes Medical Institute,
University of California San Diego, La Jolla, CA 92093-0648
ABSTRACT
growth hormone and are dwarfed. Two distinct
populations of thyrotrope cells arise during pituitary
development: a Pit-l-independent group of thyrotropes
is found transiently at the rostral tip of the gland
during early embryogenesis, whereas a second population in the caudomedial region is detectable following
activation of the pzt-l gene and persists into the
mature animal. The pit-1 gene is subject to autoregulation by its own product, and regulatory regions of
the gene contain response elements conferring activation by retinoic acid, vitamin D3 derivatives, cyclic
AMP signaling pathways, and pituitary-restricted
factors. The p i t - l gene retinoic acid response element
is entirely dependent on Pit-1 for function: this
synergistic interaction suggests a general mechanism
by which signaling molecules might achieve cellspecific effects.
Hormones secreted by the mammalian pituitary gland regulate growth, lactation,
sexual function, and homeostasis. The anterior
pituitary-specific transcription factor Pit-1 directly
activates the growth hormone, prolactin, and thyroidstimulating hormone beta genes. Dwarf animals with
defective p i t - l genes lack the thyrotrope, somatotrope,
and lactotrope cell types that express these three
genes. Similar pituitary dysfunction and short stature
are also observed in humans with mutations a t the
p i t - l locus. Pit-1 therefore is required for both the
transcriptional activation of pituitary target genes and
for survival of these three cell lineages. Pit-l-defective
animals do not express the receptor for growth
hormone- releasing factor, a key regulator of somatotrope proliferation. Mice harboring defects in the
receptor gene express significantly reduced levels of
Key Words: Growth Hormone, Prolactin, Thyroid-stimulating Hormone,
Somatotrope, Lactotrope, Thyrotrope
J. h i m . Sci. 1996. 74(Suppl. 2):94-106
Introduction
each cell type (Figure 1 ) . The five cell types ( a n d
their respective hormone products) are corticotropes
(producing adrenocorticotropin [ACTH] by proteolytic
processing of the product of the proopiomelanocortin
[POMC] gene); gonadotropes (follicle-stimulating
hormone FSH] and luteinizing hormone [LHI ); thyrotropes (thyroid-stimulating hormone [TSHI1; somatotropes (growth hormone [GHl ); and lactotropes
(prolactin [PRL]) , Follicle-stimulating hormone, LH,
and TSH are polypeptide heterodimers consisting of a
common subunit, alpha glycoprotein ( arGSU), and a
distinct 0 subunit ( FSW, LH@,TSH@).The development of the five cell types in a precise temporal order
from a common origin (Figure 1) and the physiological importance of the pituitary gland make the
anterior pituitary a n attractive system with which t o
analyze the mechanisms that regulate the commitment and subsequent differentiation of specific phenotypes during mammalian organogenesis.
The anterior pituitary arises from Rathke's Pouch,
an outfolding of embryonic ectoderm first observed a t
about embryonic d 9 of mouse development, and the
mature gland secretes polypeptide trophic hormones
that regulate growth, adrenal function, sexual activity, thyroid gland function, and lactation (Schwind,
1928; Dubois and Hemming, 1991; Voss and Rosenfeld, 1992; Andersen and Rosenfeld, 1994; Rhodes e t
al., 1994). The hormones are released from five
distinct cell types and serve as specific markers for
'We are grateful to Susan Martin and Kathleen Scully for their
assistance. SJR is a Special Fellow of the Leukemia Society of
America. MGR is an Investigator with the Howard Hughes Medical
Research Institute. Studies performed in the Rosenfeld laboratory
were supported by grants from the NIH to MGR and the Human
Growth Foundation to SJR.
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