In the posterior neural tube of vertebrate embryos, the secreted signalling
molecules Sonic hedgehog (Shh) and bone morphogenetic proteins (BMPs)
are expressed at opposite poles of the neural tube, and act antagonistically to
pattern the dorso-ventral axis of the neural tube. In contrast, in the ventral
diencephalon, in regions that will give rise to the hypothalamus, BMPs and
Shh are initially co-expressed. Subsequently, Shh shows a dynamic pattern of
expression, first undergoing a medio-Iateral expansion and then disappearing
from ventro-medial cells that will form the infundibulum.
In this study, I address how Shh is regulated within the hypothalamic
infundibulum. Using a combination of fate mapping and gene expression
analysis, I demonstrate that cells that initially co-express Shh and BMP7 give
rise to the Shh-negative infundibulum. Furthermore, I demonstrate, both in vitro
and in vivo, that BMP7 is necessary and sufficient to cause the downregulation
of Shh in the infundibulum.
Recent studies on the mouse Shh promoter (Jeong and Epstein, 2003) have
revealed that aT-box binding site is necessary for the down-regulation of Shh
in the infundibulum. Through analysis of Tbx genes, I have found that Tbx2 is
expressed in the prospective infundibulum. Furthermore, my studies reveal
that its expression is dependent on BMP activity
Finally, my studies show that, in addition to their role in regulating Shh
expression, BMPs and Tbx2 may also playa role in regulating the size of the
infundibulum. Analysis with the M-phase marker, PH3, reveals that, following
exposure to BMPs, prospective infundibular cells are transiently cell cycle
arrested, entering a synchronised cell cycle once BMP activity is lost, and Tbx2
is expressed.
Together, my results suggest that BMPs act through Tbx2 in order to control
the domain of Shh expression within the forming hypothalamus, whilst
simultaneously controlling the size of this progenitor domain.