Work in this lab is focused on how hormones create sex differences in the nervous system. During mammalian development an initially bi-potential embryo undergoes differentiation to become male or female. This process includes sexual differentiation of the central nervous system, and is driven primarily by steroid hormones produced by the developing gonads. One of the ways that hormones sculpt the developing nervous system is by controlling neuronal cell death. For example, testosterone produced by the fetal testes increases cell death in some neural regions, while decreasing death in other regions, thus leading to sex differences in neuron number.

Work in our lab is aimed at understanding how testosterone controls developmental cell death. In some cases, testosterone regulates neuronal survival by controlling the availability of neurotrophic factors.

Dr. Nancy Forger

Nancy G. Forger

Development of Neural Sex Differences: Hormones, Trophic Factors, and Cell Death

For instance, we have recently shown that we can block masculinization of a neural cell group in the spinal cord by applying antagonists to specific trophic factors. In other cases, testosterone may directly control the expression of cell death genes. In particular, we are using lab rats and several strains of transgenic mice to study the roles of Bcl-2 and related proteins in neuronal cell death.

 

We have found that a deletion of the pro-death protein, Bax, reduces or eliminates sex differences due to cell death in the brain and spinal cord. Overall, the goal of these studies is to tease apart the cellular and molecular mechanisms underlying sexually dimorphic neuronal cell death.

In addition, some projects in the lab focus on mammals, such as hyenas and naked mole rats that display unusual features of sexual differentiation. For example, female spotted hyenas are born with highly virilized genitalia, due presumably to androgen exposure in utero, and we are examining the consequences of this androgen exposure on development of the nervous system. Naked mole-rats are eusocial mammals with a strict reproductive heirarchy. We are examining changes in the nervous system that accompany the transition from "non-breeder" to breeding status.

For additional information regarding my research, teaching, and publications, please visit my Home Page.

Selected Publications:

Forger N.G., Breedlove S.M. (1986) Sexual dimorphism in human and canine spinal cord: Role of early androgen. Proc Natl Acad Sci USA 83: 7527-7531.

 
Forger N.G., Breedlove S.M. (1987) Seasonal variation in mammalian striated muscle mass and motoneuron morphology. J Neurobiology 18: 155-165.
 
Forger N.G., Breedlove S.M. (1987) Motoneuronal death during human fetal development. J Comp Neurol 264: 118-122.
 
Forger N.G., Breedlove S.M. (1992) Steroid influences on a mammalian neuromuscular system. Semin Neurosci 3: 459-468.
 
Forger N.G., Hodges L.L., Roberts S., Breedlove S.M. (1992) Regulation of motoneuron death in the spinal nucleus of the bulbocavernosus. J Neurobiol 23: 1192-1203.
 
Forger N.G., Hodges L., Breedlove S.M. (1993) The ontogeny of calcitonin gene-related peptide immunoreactivity in rat lumbar motoneurons: Delayed appearance and sexual dimorphism in the spinal nucleus of the bulbocavernosus. J Comp Neurol 330: 514-520.
 
Forger N.G., Roberts S.L., Wong V., Breedlove S.M. (1993) Ciliary neurotrophic factor rescues rat motoneurons during developmental cell death. J Neurosci 13: 4720-4726.
 
Forger N.G., Wong V., Breedlove S.M. (1995) Ciliary neurotrophic factor arrests muscle and motoneuron degeneration in androgen-insensitive rats. J Neurobiol 26: 354-362.
 
Bengston L. Lopez V., Watamura S., Forger N.G. (1996) Short- and long-term effects of ciliary neurotrophic factor on androgen-sensitive motoneurons in the lumbar spinal cord. J Neurobiol 31: 263-273.
 
Forger N.G., Galef B.G., Clark M.M. (1996) Intrauterine position affects motoneuron number and muscle size in a sexually dimorphic neuromuscular system. Brain Res 735: 119-124.
 
Forger N.G., Frank L., Breedlove S.M., Glickman S. (1996) Sexual dimorphism of perineal muscles and motoneurons in spotted hyenas. J Comp Neurol 375: 333-343.
 
Forger, N.G., Howell M.L., Bengston L., MacKenzie L., DeChiara T.M., Yancopoulos G.D. (1997) Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor. J Neurosci 17: 9605-9612.
 
Xu J., Forger N.G. (1998) Expression and androgen regulation of the ciliary neurotrophic factor receptor (CNTFRa) in muscles and spinal cord. J Neurobiol 35: 217-229.
 
Drea C.M., Weldele M.L., Forger N.G., Coscia E.M., Frank L., Licht P., Glickman S.E. (1998) Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta): 2. Effects of prenatal anti-androgens. J Reprod Fertil 113: 117-127.
 
Forger N.G., Wagner C.K., Contois M., Bengston L., MacLennan A.J. (1998) Ciliary neurotrophic factor receptor a (CNTFRa) in spinal motoneurons is regulated by gonadal hormones. J Neurosci 18: 8720-8729.
 
Forger, N.G. (1999) Psychological Sexual Differentiation, in Encyclopedia of Reproduction, E. Knobil and JD Neill, editors, Academic Press, pp. 421-430.

Fenstemaker, S.B., Zup, S.L., Frank, L.G., Glickman, S.E., and Forger, N.G. (1999) A sex difference in the hypothalamus of spotted hyenas. Nature Neuroscience, 2:943-945.

Park J.J., Howell M., Winseck A., Forger N.G. (1999) Effects of testosterone on the development of a sexually dimorphic neuromuscular system in ciliary neurotrophic factor receptor knockout mice. J. Neurobiology, 41:317-325.

Varela, C.R., Bengston, L, Xu, J., MacLennan, A.J., and Forger, N.G. (2000) Additive effects of ciliary neurotrophic factor and testosterone on motoneuron survival; Differential effects on motoneuron size and muscle morphology. Exp. Neurol., 165:384-393.

Peroulakis, M.E., and Forger, N.G. (2000) Ciliary neurotrophic factor increases muscle fiber number in the developing levator ani muscle of female rats. Neurosci. Letts., 296:73-76.

Xu, J., Gingras, K.M., Bengston, L., Di Marco, A., Forger, N.G. (2001) Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons. J. Neurosci. 21:4366-4372.

Forger, N. G. (2001) The development of sex differences in the nervous system. In: The Handbook of Behavioral Neurobiology, Vol. 13: Developmental Psychobiology . E. Blass, editor, Plenum, New York, pp. 153-208.

Zup S.L., and Forger N.G. (2002) Hormones and sexual differentiation. In: Encyclopedia of the Human Brain, V.S. Ramachandran, editor, Academic Press, pp 323-341.

Peroulakis, M.E., Goldman, B., and Forger, N.G. (2002) Perineal muscles and motoneurons are sexually monomorphic in the naked mole-rat (Heterocephalus glaber). J. Neurobiol., 51:33-42.

Park J.J., Zup, S.L., Verhovshek, T, Sengelaub D.R., Forger N.G. (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, 53:403-412.

Zup S.L., Forger N.G. (2002) Testosterone regulates Bcl-2 immunoreactivity in a sexually-dimorphic motor pool of adult rats. Brain Research, 950:312-316.

Zup S.L., Carrier H, Waters, E.M., Tabor A, Bengston L., Rosen G.J., Simerly R.B., Forger N.G. (2003) Overexpression of Bcl-2 reduces sex differences in neuron number in the brain and spinal cord. J. Neuroscience, 23:2357-2362.

Forger N.G., Prevette D, deLapeyriere O, de Bovis B, Wang S, Bartlett P, Oppenheim R.W. (2003) Cardiotrophin-like cytokine / cytokine-like factor 1 (CDC/CLF) is an essential trophic factor for lumbar and facial motoneurons in vivo. Journal of Neuroscience 23:8854-8858.

Forger N.G., Rosen G.J., Waters E.M., Jacob D., Simerly R.B., de Vries G.J. (2004) Deletion of Bax eliminates sex differences in the mouse forebrain. Proc. Natl. Acad. Sci. 101:13666-13671.

Jacob D.A., Bengston C.L., Forger N.G. (2005) Effects of Bax gene deletion on muscle and motoneuron degeneration in a sexually dimorphic neuromuscular system. Journal of Neuroscience 25:5638-5644.

Forger N.G. (2005) Cell death and sexual differentiation of the nervous system. Neuroscience, in press.

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