Donald D. Brown Professor Department of Embryology, Carnegie Institution of Washington Adjunct Professor Department of Biology CMDB Graduate Program Faculty M.S. University of Chicago M.D. University of Chicago

[Research Interests] [Representative Publications] [Lab Members]

RESEARCH INTERESTS

Amphibian Metamorphosis

Metamorphosis in frogs and toads is a set of complex developmental programs controlled by thyroid hormone (TH). The pervasive and dramatic changes that occur as a tadpole turns into a frog have captured the attention of life scientists from many disciplines. For evolutionary biologists, the extent to which related organisms incorporate metamorphosis in their life cycle is of paramount interest. For specialists who study cell death, a burgeoning field of research interest, apoptosis is a major event in metamorphosis. It can be induced in many tissues, even in whole organs, by TH. For endocrinologists, TH-induced metamorphosis is a model for the general problem of the molecular basis of TH action and the interaction of the hypothalamus, the pituitary, and the thyroid glands. However, the emphasis in our laboratory is the use of amphibian metamorphosis to study complex developmental programs such as vertebrate organogenesis which can be initiated by the simple addition of TH to the tadpole's rearing water.

A developmental program is effected through the expression of many genes, causing changes in phenotype. The traditional way to study complex programs has been to identify mutants that change the phenotype. However, there are many important programs that one would like to study in organisms that are not suitable for traditional genetics. This list includes vertebrate organo-genesis, amphibian metamorphosis, tissue and organ regeneration, changes afterbirth in mammals, diseased versus normal tissues, the action of hormones or drugs on their target tissues or organs, and the influence of various environmental stimuli on a particular organ.

The later that a program is expressed in the life cycle of any organism, including those suited for genetics, the more difficult it will be to use traditional genetics. An alternative approach to the analysis of complex programs utilizes molecular biological methods which isolate and identify genes whose expression change as the programs are executed.

We have developed a three phase strategy that is generally applicable to the analysis of complex programs, using TH induced metamorphosis in Xenopus as a model. First, a subtractive hybridization method coupled with PCR finds the up- and down-regulated genes. Second, the genes are sequenced and identified through a database search. Finally, functional assays must be devised to test directly the role of the genes in the program. The subtractive method used in these experiments has two useful features. It finds genes that are expressed at the low levels that are expected for transcription or growth factors. More importantly the method gives an estimation of the program' s complexity much as does a genetic screen. Whereas, a genetic screen identifies a gene by its function, there is no guarantee that a gene plays a key role in a program simply because it is up- or down-regulated. Therefore, genes suspected to influence the program must be tested for function.

REPRESENTATIVE PUBLICATIONS

Huang, H., Cai, L. Remo, B. and Brown, D.D.  2001. Timing of Metamorphosis and the Onset of the Negative Feedback Loop between the Thyroid Gland and the Pituitary is Controlled by the Type II Iodothyronine Deiodinase in Xenopus laevis. Proc. Nat. Acad. Sci.  In press.

Huang, H. and Brown, D.D. 2000. Overexpression of Xenopus laevis growth hormone stimulates growth of tadpoles and frogs. Proc. Nat. Acad. Sci. 97:190-194.

Huang, H., and Brown, D.D. 2000. Prolactin is not a juvenile hormone in Xenopus laevis metamorphosis. Proc. Nat. Acad. Sci. 97:195-199.

Huang, H., Marsh-Armstrong, N., and Brown, D.D. 1999. Metamorphosis is inhibited in transgenic Xenopus laevis tadpoles that over-express type III deiodinase. Proc. Nat. Acad. Sci. 96: 962-967.

Furlow, J.D. and Brown, D.D. 1999. In vivo and in vitro analysis of the regulation of a transcription factor gene by thyroid hormone during Xenopus laevis metamorphosis. Mol. Endocrinol. 13: 2076-2089.

Elinson, R.P., Remo, B., Brown, D.D. 1999. Novel structural elements during tail resorption in Xenopus metamorphosis: lessons from tailed frogs. Dev. Biol. 215: 243-252.

Marsh-Armstrong, N., Huang, H., Berry, D.L. and Brown, D.D. 1999. Germline transmission of transgenes in Xenopus laevis Proc. Nat. Acad. Sci. 96:14389-14393.

Marsh-Armstrong, N. Huang, H., Remo, B.F., Liu, T.T. and Brown, D.D. 1999. Asymmetric growth and development of the Xenopus laevis retina during metamorphosis is controlled by type-III deiodinase.  Neuron. 24:871-878.

Berry, D., Scwartzman,R. and Brown, D.D. 1998. The expression pattern of thyroid hormone response genes in the tadpole tail identifies multiple resorption programs. Dev. Biol. 203:12-23.

Berry, D., Rose,C., Remo, B., and Brown, D.D. 1998. The expression pattern of thyroid hormone genes in remodeling tadpole tissue defines distinct growth and resorption gene expression programs. Dev. Biol. 203: 24-35.

Furlow, J. D., Berry D. L. , Wang, Z. and Brown, D. 6D. 1997. A set of novel tadpole specific genes expressed only in the epidermis are down-regulated by thyroid hormone during Xenopus laevis metamorphosis, Dev. Biol. 182:284-298.

Brown, D.D. 1997. The role of thyroid hormone in zebrafish and axolotl development. Proc. Nat. Acd. Sci. USA 94, 13011-13016.

Brown, D. D., Wang, Z., Furlow, J. D., Kanamori, A., Schwartzman, R. A., Remo, B. F., and Pinder, A. 1996. The thyroid hormone-induced tail resorption program during Xenopus laevis metamorphosis. Proc. Natl. Acad. Sci. 93:1924-1929.

Eliceiri, B. P. and Brown, D. D. 1994. Quantitation of endogenous thyroid hormone receptors alpha and beta during embryogenesis and metamorphosis in Xenopus laevis. J. Biol. Chem. 269:24459-24465.

Wang, Z., and Brown, D. D. 1993. The thyroid hormone-induced gene expression program for amphibian tail resorption. J. Biol. Chem. 268:16270-16278 .

Kanamori, A. and Brown, D. D. 1992. The regulation of thyroid hormone receptor b genes by thyroid hormone in Xenopus laevis. J. Biol. Chem. 267:739-745.

Wang, Z. and Brown, D. D. 1991. A gene expression screen. Proc. Natl. Acad. Sci. USA 88:11505-11509.

Yaoita, Y. and Brown, D. D. 1990. A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis. Genes and Develop.4:1917-1924.

Yaoita, Y., Shi, Y.-B., and Brown, D. D. 1990. Xenopus laevis a and b thyroid hormone receptors. Proc. Natl Acad. Sci. USA 87:7090-7094.

Lab Members

Postdoctoral Fellows:
Biswajit Das, Liquan Cai, Alexander Schreiber
 
Graduate Students:

Technicians/Staff:
Rejeanne Juste 

Heather Henry