ANDROGEM REGULATION OF NEUROMUSCLAR FUNCTION

点击翻译按钮获取中文摘要

Our goal is an understanding of the cellular and molecular mechanisms responsible for central nervous system sexual differentiation. The present proposal explores the contribution of the masculinized periphery - muscle and neuromuscular junction - to this process. Our experimental system is the laryngeal muscle of Xenopus laevis, a sexually dimorphic, androgen-target muscle innervated by sexually dimorphic, androgen-target motor neurons. We have established that the marked sex difference in muscle fiber number of the adult is due to androgen-induced myogenesis during a limited developmental period. The goal of the proposed experiments is to determine the cellular basis of this process, clarify the role and site of action of androgenic steroids and determine whether the process of masculinization includes sexual differentiation of the neuromuscular junction. We will examine myoblast induction, survival and differentiation during male and female development in vivo and in vitro. Androgen receptor expression will be measured using binding assays and steroid autoradiography. Cell types will be identified from electron micrographs and by antibody and in situ hybridization labeling. The role of innervation in myoblast sexual differentiation will be studied by blocking muscle activity and by nerve section. We will characterize the development of synaptic innervation in males and females morphologically and examine acetylcholine receptor distribution. We believe that the sexual differentiation of motor neurons is regulated, at least in part, by masculinization of the periphery. Androgens can effect the development of sexual dimorphisms by gaining access to certain key developmental processes -- cell specification, survival, differentiation, and cell to cell contacts. We plan to determine how steroid hormones exert these effects and why some are limited to certain key developmental stages or "critical" periods. These questions are key to unravelling how the brain develops and the neural and endocrine differences that underlie the increased vulnerability of males to developmental abnormalities including some neuromuscular diseases, aphasias and affective disorders.