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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS019949-04
Application #
3400083
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1983-07-01
Project End
1989-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Graduate Schools
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Perez, J; Kelley, D B (1997) Androgen mitigates axotomy-induced decreases in calbindin expression in motor neurons. J Neurosci 17:7396-403
Kelley, D B (1997) Generating sexually differentiated songs. Curr Opin Neurobiol 7:839-43
Cohen, M A; Kelley, D B (1996) Androgen-induced proliferation in the developing larynx of Xenopus laevis is regulated by thyroid hormone. Dev Biol 178:113-23
Perez, J; Cohen, M A; Kelley, D B (1996) Androgen receptor mRNA expression in Xenopus laevis CNS: sexual dimorphism and regulation in laryngeal motor nucleus. J Neurobiol 30:556-68
Robertson, J C; Kelley, D B (1996) Thyroid hormone controls the onset of androgen sensitivity in the developing larynx of Xenopus laevis. Dev Biol 176:108-23
Perez, J; Kelley, D B (1996) Trophic effects of androgen: receptor expression and the survival of laryngeal motor neurons after axotomy. J Neurosci 16:6625-33
Kang, L; Marin, M; Kelley, D (1995) Androgen biosynthesis and secretion in developing Xenopus laevis. Gen Comp Endocrinol 100:293-307
Tobias, M L; Marin, M L; Kelley, D B (1993) The roles of sex, innervation, and androgen in laryngeal muscle of Xenopus laevis. J Neurosci 13:324-33
Fischer, L; Catz, D; Kelley, D (1993) An androgen receptor mRNA isoform associated with hormone-induced cell proliferation. Proc Natl Acad Sci U S A 90:8254-8
He, W W; Fischer, L M; Sun, S et al. (1990) Molecular cloning of androgen receptors from divergent species with a polymerase chain reaction technique: complete cDNA sequence of the mouse androgen receptor and isolation of androgen receptor cDNA probes from dog, guinea pig and clawed frog. Biochem Biophys Res Commun 171:697-704

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