The endocrine-secreting lobe of the pituitary gland, or adenohypophysis, forms from
cells at the anterior margin of the neural plate through inductive interactions involving
secreted morphogens of the Hedgehog (Hh), fibroblast growth factor (FGF), and bone
morphogenetic protein (BMP) families. To better understand when and where Hh signaling
influences pituitary development, we have analyzed the effects of blocking Hh signaling
both pharmacologically (cyclopamine treatments) and genetically (zebrafish Hh pathway
mutants). While current models state that Shh signaling from the oral ectoderm patterns
the pituitary after placode induction, our data suggest that Shh plays a direct early
role in both pituitary induction and patterning, and that early Hh signals comes from
adjacent neural ectoderm. We report that Hh signaling is necessary between 10 and
15 h of development for induction of the zebrafish adenohypophysis, a time when shh
is expressed only in neural tissue. We show that the Hh responsive genes ptc1 and
nk2.2 are expressed in preplacodal cells at the anterior margin of the neural tube
at this time, indicating that these cells are directly receiving Hh signals. Later
(15-20 h) cyclopamine treatments disrupt anterior expression of nk2.2 and Prolactin,
showing that early functional patterning requires Hh signals. Consistent with a direct
role for Hh signaling in pituitary induction and patterning, overexpression of Shh
results in expanded adenohypophyseal expression of lim3, expansion of nk2.2 into the
posterior adenohypophysis, and an increase in Prolactin- and Somatolactin-secreting
cells. We also use the zebrafish Hh pathway mutants to document the range of pituitary
defects that occur when different elements of the Hh signaling pathway are mutated.
These defects, ranging from a complete loss of the adenohypophysis (smu/smo and yot/gli2
mutants) to more subtle patterning defects (dtr/gli1 mutants), may correlate to human
Hh signaling mutant phenotypes seen in Holoprosencephaly and other congenital disorders.
Our results reveal multiple and distinct roles for Hh signaling in the formation of
the vertebrate pituitary gland, and suggest that Hh signaling from neural ectoderm
is necessary for induction and functional patterning of the vertebrate pituitary gland.