Deborah J. Good

 

Molecular Neurobiology-Regulation of Body Weight,
Reproduction and Locomotion

In the United States, nearly 65% of the adult population is overweight or obese. Obesity (BMI > 30) has increased 50% in the last twenty years. My laboratory is interested in the role of the basic helix-loop-helix transcription factor, Nhlh2 in body weight regulation. We have found that targeted deletion of this transcription factor in mice results in adult-onset obesity and infertility. The Nhlh2 knockout mice (N2KO) become obese, not because they overeat, but rather because they do not exercise. Our laboratory is trying to identify signals that activate this transcription factor, as well as genes that are regulated by this transcription factor in the brain. We have shown that signals of energy excess (leptin, food intake) result in increased hypothalamic expression of Nhlh2. We have also shown that genes such as prohormone convertase, which are regulated by Nhlh2, do not turn on in response to food intake or leptin in N2KO mice. Thus, we are characterizing the signaling pathways that involve Nhlh2 and its target genes in the regulation of body weight. These can be used for a better understanding of the biological and molecular basis of obesity, as well as identification of potential target proteins for pharmaceutical interventions in weight control. In other work from our laboratory, we are using human volunteers to discover polymorphisms in the Nhlh2 which may predispose them to obesity. We are also using different breeds of cattle with different fat contents to identify polymorphisms in Nhlh2 which could be used to genetically select high fat and lower fat beef.

Targeted deletion of Nhlh2 in mice also results in hypogonadism and infertility. We have shown that sperm counts and oocytes are reduced more than 50% in N2KO mice. The sperm and eggs from the mutant animals are fully competent for fertilization and development, as in vitro fertilization rates and blastocyst formation are nearly identical to those using eggs and sperm from normal mice. Thus, reduced gamete numbers cannot account for infertility in these animals. We have shown that both male and female N2KO mice lack normal sexual behavior, indicating that this phenotype most likely contributes to infertility in these mutant animals. We are characterizing the molecular signaling pathways that lead to lack of sexual behavior in these animals and have found evidence that regulation of the estrogen and progesterone receptors in the brain may be altered in N2KO mice. These data will help to characterize the neuroendocrine signaling pathways that control fertility through sexual behavior.

Lab Members:
Postdoctoral Fellow: Amy Burnside

Graduate students: Dana Fox, Kristen Vella

Technician: Chris Coyle, Alison Miller Bardwell

Undergraduates: Natasha Pogue, Adwoa Tetebea

For additional information, please visit my Veterinary and Animal Sciences Laboratory Web Page.

UMass Magazine Summer 2003 article "Tiny couch potatoes...Deborah Good's mice are fat, lazy and undersexed".

 

 

Adult onset obesity in Nhlh2 knockout mice occurs by 12 weeks of age. Note that at 8 weeks of age, both the normal and knockout mice are similar in weight and body structure, but older Nhlh2 knockout animals have an obvious increase in abdominal fat and body weight.

 

Representative Publications:

Good, D. J., Porter, F.D., Mahon, K.A., Parlow, A.F., Westphal, H. and Kirsch, I.R. (1997) Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nature Genetics 15(4): 397-401. MEDLINE

Izraeli, S., Lowe, L., Bertness, V., Good, D.J., Kuehn, M.R., and Kirsch, I.R (1997) SIL, a gene commonly disrupted in T-cell acute lymphoblastic leukemia, encodes a cell cycle regulated cytosolic protein which is critical for embryonic development. Blood 90: 387a.

Izraeli, S., Lowe, L., Bertness, V., Good, D.J., Kuehn, M.R., and Kirsch, I.R. (1997) The immediate early gene SIL is required for embryonic development and determination of left/right axis. Dev. Biol. 186: B93

Good, D.J. (1998) Obesity…is it all in your head? Accents 2:1-2.

Izraeli, S., Lowe, L.A., Bertness, V. L., Good, D.J., Dorward, D.W., Kirsch, I.R., and Kuehn, M.R., (1999) The SIL gene is required for mouse embryonic axial development and left-right specification, Nature, 399: 691-694. MEDLINE

Good, D.J. (2000) How tight are your genes? Transcriptional and post-transcriptional regulation of the leptin receptor, NPY, and POMC genes. Hormones and Behavior 37: 284-298. MEDLINE

Good, D.J., Jing, E., Coyle, C.A., Powers, B. and Wade, G. (2000) Mechanism of obesity in the Nhlh2 transcription factor knockout mouse. Obesity Research 8: Suppli.1 15S.

Good, D.J.*, Cogliati, T.*, Delgado-Romero, P., Czaja, J., Eckhaus, M.A., Shotwell, K.F., Koch, W.J., Haigney, M., and Kirsch, I.R. (2001) Sudden cardiac death and autonomic dysfunction in Nhlh1 null mice *both authors contributed equally to this paper, submitted to Nature Medicine and under review

Cogliati, T., Delgado, P., Haigney, M., Good, D.J., and Kirsch, I.R., (2001) Multiple neurologic phenotypes in mice null for the bHLH neurogenic transcription factors Nhlh1 and Nhlh2, Proceedings of the Society for Neuroscience Meeting, submitted

Marin-Bivens, C., Kurokawa, M., Fissore, R., and Good, D.J., (2001) Ovulatory and behavioral abnormalities underleie diminished fertility in female mice with targeted deletion of the hypothalamic transcription factor, Nhlh2, Proceedings of the Society for Neuroscience, submitted.

Jing, E. and Good, D.J. (2001) Decreased prohormone convertase mRNA and POMC protein contribute to obesity in Nhlh2 knockout mice, in revision.

Miele, M., Marin-Bivens, C., Kurokowa, M., Fissore, R., and Good, D.J. (2001) Perturbations in oocyte development, ovulation, and estrous cyclicity underlie reproductive dysfunction in female mice lacking the gene for transcription factor Nhlh2, in preparation.

Marin-Bivens, C., Kurokawa, M., Fissore, R., and Good, D.J., (2001) Hyporesponsiveness to steroid hormones contributes todiminished fertility in female mice with targeted deletion of the hypothalamic transcription factor Nhlh2, in preparation

Cogliati T, Good DJ, Haigney M, Delgado-Romero P, Eckhaus MA, Koch WJ, Kirsch IR. (2002) Predisposition to arrhythmia and autonomic dysfunction in Nhlh1-deficient mice. Mol Cell Biol 22:4977-4983.

Coyle C.A., Jing E., Hosmer, T., Powers B., Wade, G., and Good, D.J., (2002) Reduced activity preceeds adult-onset obesity in Nhlh2 knockout mice. Physiol. Behav.,77: 387-402.

Jing E., Nillni, E.A., Sanchez, V.C., Stuart, R., and Good, D.J., (2004) Reduced levels of hypothalamic prohormone convertase I mRNA in obese the Nhlh2 transcription factor knockout mouse. Endocrinology, accepted (subject of a News and Views editorial)

Good, D.J. (2004) The use of Flash animations within a WebCT environment: Enhancing comprehension of experimental procedures in a biotechnology laboratory, accepted

Johnson, S.A., Miele, M., Marin-Bivens, C., Coyle, C.A., Fissore, R., and Good, D.J., (2004) The Nhlh2 transcription factor is required for female sexual behavior and reproductive longevity, Hormones and Behavior, proof online


  Back to the Faculty Index