I am a visiting scholar from the University of Padua, where I was enrolled in a PhD program in "Clinical Methodology and Endocrine Sciences", part of the School of Medical, Clinical and Experimental Sciences under the mentorship of dr. Franco Mantero. In Dr. Mantero's lab, I was studying the effects of somatostin analogues on adrenal tumors and on the angiogenesis, in particular of SOM230 on adrenocortical carcinomas, cortisol-secreting adenomas and aldosterone-secreting adenomas. I joined the Hammer lab in November 2008, through the International Endocrine Scholar Program (IESP) of the Endocrine Society. I currently am working on the effects of the disregulation of Sonic hedgehog's pathway in the adrenal gland.
Sonic Hedgehog pathway and the adrenal
Sonic hedgehog (Shh) is a secreted ligand, one of the three Hedgehog ligands: Sonic, Desert and Indian. They are expressed in several regions of the body, alone or in combinations of two or three. In the adrenal gland, Sonic hedgehog is the prominently expressed ligand. The ligand can bind to the transmembrane Patched family receptors (named Ptch1 and Ptch2) to release the G protein-coupled receptor Smoothened (Smo) signal transduction from Patched-dependent suppression. Smo activates STK36 serine/threonine kinase to stabilize Gli family members (Gli1, Gli2 and Gli3) for nuclear translocation. Hedgehog signaling activates Gli-dependent transcription of target genes.
Scheme of the Hedgehog pathway (right) and expression of Shh, Ptch and Gli1 in adrenal gland showed by Beta-galactosidase activity revelation.
Many studies investigated the role of the Hh pathway in the development. Mice lacking Shh die perinatally and mice homozygous for a mutated form of Shh showed several developmental defects similar to those seen in human patients with conditions such as cyclopia, craniofacial dysmorphism, and abnormal tissue patterning (Chiang et al., 1996). Patients with Pallister-Hall syndrome, a syndrome caused by a frameshift mutation in Gli3 (Kang et al., 1997), were diagnosed with hypoadrenalism. Transgenic mice carrying a similar mutation resulted in a phenotype with many of the developmental abnormalities characterizing the Pallister-Hall syndrome, including adrenal agenesis (Bose et al., 2002). Mutations in Hh pathway can result in holoprosencephaly and these patients often present with adrenal insufficiency (Begleiter and Harris, 1980; Dubourg et al., 2007).
In the skin, an organ with an high cell renewal rate, Shh is involved in hair follicle morphogenesis and in adult hair cycle. Due to the importance of this pathway, its disregulation is found in different pathologies: activating mutations in Smo have also been detected in sporadic BCCs (Xie et al. 1998), and overexpression of Shh, Smo, Gli1, or Gli2 leads to BCCs in mice (Dahmane et al. 1997; Grachtchouk et al. 2000, 2003; Hutchin et al. 2005; Oro et al. 1997; Xie et al. 1998).
Confirming previous studies (Ching S. et al., 2009; King P. et al., 2009; Huang CC et al., 2010), we found Shh expressing cells located in the subcapsular region of the mouse adrenal cortex, whereas the Ptch-positive cells and the Gli1-positive cells in a thin layer in the adrenal capsule. Interestingly, these already cited studies investigated the role of Shh in adrenal development and observed that Shh is required for the adrenal organogenesis. In fact, the loss of Shh in the adrenal cortex caused reduced proliferation of capsular cells and a reduction in capsular thickness and in adrenal size, but did not affect the adrenal zonation and the ability to produce steroids. Shh-expressing cells also generate all steroidogenic cell types, but not the non-steroidogenic ones. Lineage tracing studies showed that Gli1-positive cells, cells responding to the Shh signaling, are organized in clusters in the adrenal capsule and can migrate centripetally into the cortex giving rise to cells of the adrenal cortex.
My project is focused on the study of the Gli1-expressing cells in the adrenal capsule and how they react to a disregulated Hh signaling. I am examining changes in adrenal morphology caused by overactivation of Hh pathway and on the possible effects on other pathways involved in the adrenal ontogenesis, i.e. Wnt pathway.