|Nancy G. Forger
Professor of Psychology, University of Massachusetts
Ph.D.: University of California at Berkeley
Development of Neural Sex Differences; Hormones and Neurotrophic Factors
During mammalian development an initially bi-potential embryo undergoes differentiation to become male or female. This process proceeds primarily under the control of gonadal steroid hormones and includes sexual differentiation of the nervous system. Work in this lab is focused on understanding how steroid hormones influence neural development.
We study a simple neuromuscular system which is sexually dimorphic in many mammals, including humans. Motor neurons of the spinal nucleus of the bulbocavernosus (SNB) reside in the lumbar spinal cord and innervate striated muscles attached to the phallus. Adult males have many more SNB motoneurons than do females, and the sex difference comes about as a result of hormone-regulated cell death. SNB motoneurons and their target muscles initially develop in both sexes. Testosterone keeps the muscles and motoneurons alive in males, while they degenerate in females. The SNB neuromuscular system of a female rat can be completely masculinized by treating her with androgens around the time of birth.
We have found that, like androgens, ciliary neurotrophic factor (CNTF) can rescue SNB motoneurons and their target muscles in newborn female rats. In addition, the normal sex difference in the spinal cord does not develop in mutant mice lacking the CNTF receptor. We are currently exploring the hypothesis that CNTF, or other trophic factors, mediate the effects of androgens in the developing SNB neuromuscular system.
Jacob DA, Bengston CL, Forger NG (2005) Effects of Bax gene deletion on muscle and motoneuron degeneration in a sexually dimorphic neuromuscular system. Journal of Neuroscience 25:5638-5644.
Forger NG, Rosen GJ, Waters EM, Jacob D, Simerly RB, de Vries GJ (2004) Deletion of Bax eliminates sex differences in the mouse forebrain. Proc Natl Acad Sci U S A. 101: 13666-13671.
Forger NG, Prevette D, deLapeyriere O, de Bovis B, Wang S, Bartlett P, Oppenheim RW (2003) Cardiotrophin-Like Cytokine/Cytokine-Like Factor 1 is an Essential Trophic Factor for Lumbar and Facial Motoneurons In Vivo J. Neurosci. 23:8854-8858.
Zup SL, Carrier H, Waters, EM, Tabor A, Bengston L, Rosen GJ, Simerly RB, Forger NG (2003) Overexpression of Bcl-2 reduces sex differences in neuron number in the brain and spinal cord. Journal of Neuroscience 23:2357-2362.
Zup SL, Forger NG (2002) Testosterone regulates Bcl-2 immunoreactivity in a sexually-dimorphic motor pool of adult rats. Brain Res, 950:312-316.
Park JJ, Zup, SL, Verhovshek, T, Sengelaub DR, Forger NG (2002) Castration reduces motoneuron soma size but not dendritic length in the spinal nucleus of the bulbocavernosus of wild-type and Bcl-2 overexpressing mice. J Neurobiol. 2002 Nov 15;53(3):403-12.
Peroulakis, M. E., B. Goldman and N. G. Forger (2002). "Perineal muscles and motoneurons are sexually monomorphic in the naked mole-rat (Heterocephalus glaber)." J Neurobiol 51(1): 33-42.
Xu, J., K. M. Gingras, L. Bengston, A. Di Marco and N. G. Forger (2001). "Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons." J Neurosci 21(12): 4366-72.
Varela, C. R., L. Bengston, J. Xu, A. J. MacLennan and N. G. Forger (2000). "Additive effects of ciliary neurotrophic factor and testosterone on motoneuron survival; differential effects on motoneuron size and muscle morphology." Exp Neurol 165(2): 384-93.
Peroulakis, M. E. and N. G. Forger (2000). "Ciliary neurotrophic factor increases muscle fiber number in the developing levator ani muscle of female rats." Neurosci Lett 296(2-3): 73-6.
Park, J. J., M. Howell, A. Winseck and N. G. Forger (1999). "Effects of testosterone on the development of a sexually dimorphic neuromuscular system in ciliary neurotrophic factor receptor knockout mice." J Neurobiol 41(3): 317-25.
Drea, C. M., M. L. Weldele, N. G. Forger, E. M. Coscia, L. G. Frank, P. Licht and S. E. Glickman (1998). "Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 2. Effects of prenatal anti-androgens." J Reprod Fertil 113(1): 117-27
Forger, N. G., C. K. Wagner, M. Contois, L. Bengston and A. J. MacLennan (1998). "Ciliary neurotrophic factor receptor alpha in spinal motoneurons is regulated by gonadal hormones." J Neurosci 18(21): 8720-9.
Xu, J. and N. G. Forger (1998). "Expression and androgen regulation of the ciliary neurotrophic factor receptor (CNTFRalpha) in muscles and spinal cord." J Neurobiol 35(2): 217-25.
Forger, N.G., Howell, M.L., Bengston, L., MacKenzie, L., DeChiara, T.M. and Yancopoulos, G.D. (1997) Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor. J. Neuroscience 17, 9605-9612.
Forger, N.G., Frank, L.G., Breedlove, S.M. and Glickman, S.E. (1996) Sexual dimorphism of perineal muscles and motoneurons in spotted hyenas. J. Comp. Neurol. 375, 333-343.