Sonic hedgehog signaling pathway in normal and adenomatous pituitary

This work investigates for the first time the expression and the
role of Sonic hedgehog signaling pathway in adult pituitary and in
pituitary tumors. Shh is a signaling protein, important in
regulating patterning and proliferation in the embryo and the
adult. It has a crucial role in pituitary development and Shh
deficient mice do not even have a rudimentary Rathke's pouch (the
development structure that gives rise to anterior pituitary). This
study reveals the presence of an active Shh pathway in the
post-developmental pituitary gland, with major impacts on hormone
secretion and cell proliferation. After embryonic development, Shh
continues to be expressed in the normal adult pituitary, being
mainly co-localized in corticotrophs. These cells express also the
receptor Ptc2 and the Shh induced transcription factor Gli1, being
so Shh-producing and Shh-responsive cells. Shh acts in an autocrine
way inside corticotrophs, inducing a major stimulation of ACTH
secretion in the normal rat pituitary and in the AtT-20 cell line.
The Shh induced ACTH secretion effect is synergistic with CRH. Shh
stimulation increases CRH-R1 levels, up-regulating so the response
of corticotrophs to CRH. At the same time, Gli1 is not only
activated by Shh, but also by CRH and PKA. Gli1 itself activates
POMC-transcription and acts in parallel upstream to CREB and AP-1.
A major increase in Shh protein levels is seen as a result of CRH
stimulation. All these results put in evidence a multiple
cross-talk between these two important pathways acting at different
levels to insure the final ACTH stimulation. Other types of
hormone-secreting adenohypophysial cells possess one of Shh
receptors (Ptc1 or Ptc2) and the transcription factor Gli1, so they
have an active Shh pathway. Shh produced in the corticotrophs is a
signaling protein, so it diffuses and acts also in distance. Shh
increases GH secretion from the rat pituitary somatotrophs and from
the GH3 cell line, while the effect on Prolactin is not
statistically significant. The Sonic hedgehog pathway is
downregulated in pituitary adenomas. Screening of 55 pituitary
tumors reveals that they have a significantly reduced expression of
Shh and Gli1. Although Shh in the normal pituitary is secreted by
corticotroph cells, all the Cushing tumors screened had no Shh
expression at all. Cell culture experiments performed in the AtT-20
corticotroph cell line in vitro show that Shh reduces cell
proliferation by 50% and this effect is partially reducible by
Cyclopamine. So Shh maintains the low proliferative capacity of
corticotrophs in the normal pituitary gland and its loss may be one
of the factors leading to tumor progression. It is concluded that
Shh is produced in the anterior pituitary gland, is a major
stimulant of ACTH and GH secretion, acts synergistically with CRH,
opposes corticotroph cell proliferation and is downregulated in
pituitary adenomas.