Lineage conversion of differentiated cells in response to hormonal feedback has yet to be described. To investigate this we are studying the adrenal cortex, which is composed of functionally distinct concentric layers that develop postnatally, the outer zona Glomerulosa (zG) and the inner zona Fasciculata (zF). These layers have separate functions and are continuously renewed in response to physiological demands regulated by discrete hormonal feedback loops. Their cellular origin, lineage relationship and renewal mechanism, however, remain poorly understood. It has been proposed that differentiated zG cells undergo lineage conversion into zF cells. Cell fate mapping and gene deletion studies using zG-specific Cre expression confirmed this hypothesis and established lineage conversion is dependent on the master transcriptional regulator Steroidogenic Factor 1 (SF1). These findings demonstrate that adrenocortical zonation results from lineage conversion and may provide a paradigm for homeostatic cellular renewal in other tissues. This proposal seeks to define the cellular and molecular mechanisms underlying lineage conversion using lineage-tracing, lineage-induction, gene deletion, gene stabilization, and hormonal and circadian analyses. Specifically, we will characterize the effect on lineage conversion and adrenal homeostasis of modifying SF1 signaling and its downstream targets, including the canonical Wnt/?-catenin signaling pathway and the intrinsic adrenal clock.

Public Health Relevance

The adrenal gland produces stress hormones required for survival. Throughout life the cells that produce these hormones are continually replaced through mechanisms that are poorly understood. Using a new mouse model that allows for the marking and manipulation of these cells, this proposal focuses on identifying how hormone-producing cells are replaced and regulated. Results from these studies may have important implications for the future treatment of diseases such as congenital adrenal hyperplasia, Cushing's syndrome, hypertension and cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK100653-02
Application #
8733164
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115