MECHANISMS OF ADRENAL CORTEX GROWTH/DIFFERENTIATION

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (taken from the application) Mechanisms governing steroidogenesis and the development and differentiation of steroidogenic organs, namely the adrenal glands and gonads, remain a fundamental question in mammalian biology. A functional adrenal cortex is essential for life as evidenced by the early death of patients with congenital adrenal hypoplasia or adrenal steroid deficiencies. Recently, the orphan nuclear receptor Steroidogenic factor-1 (SF-1) has been shown to be essential for both gonadal and adrenal development, as evidenced in SF-1 null mice that lack adrenal glands, gonads and the gonadotrope cell type of the pituitary gland. Work in this laboratory has focused on the mechanisms by which SF-1 is activated to initiate adrenal-specific growth and differentiation. Activation by extracellular signals is central to the functioning of the adrenal cortex and steroidogenic output. Recent work in this laboratory has revealed that membrane signals leading to mitogen-activated protein kinase activation induce phosphorylation and subsequent activation of SF-1. This phosphorylation leads to recruitment of nuclear receptor cofactors to the transcriptional machinery and subsequent target gene transcriptional initiation. In this manner, SF-1 integrates hormonal stimulation of the adrenal cortex with gene transcription and ultimate steroid output. The phenotype created in the SF-1 null mice is reminiscent of the clinical syndromes of X-linked congenital adrenal hypoplasia caused by mutations in the DAX-1 gene (another orphan nuclear receptor). The recent description of a heterozygous SF- 1 mutation in a patient with adrenal insufficiency raises the possibility that in addition to phosphorylation, SF-1 gene dosage is critical for the adrenal developmental and steroidogenic programs. In this one-year application, I propose to examine the SF-1 heterozygous (+/-) mice for adrenal growth and differentiation defects to begin to clarify the dual roles of SF-1 in the proliferative and steroidogenic responses of the adrenal cortex. Preliminary experiments reveal that like the heterozygous SF-1 patient, the heterozygous SF-1 (+/-) mice have adrenal insufficiency with smaller adrenal glands and diminished steroidogenic output in response to restraint stress. Therefore, in vivo, SF-1 is critical for both the proliferative and differentiated function of the adrenal cortex. The goal of this proposal is to utilize the SF-1 heterozygous mice to begin to understand the role of SF-1 in various adrenal growth models and stress paradigms. As discussed in the body of this proposal, this data will provide valuable tools to allow for the search for SF- 1 target genes and cofactors important for these processes.