Douglas Forrest, PhD
- ADJUNCT ASSOCIATE PROFESSOR | Genetics and Genomic Sciences
PhD, University of Glasgow
Nuclear Preceptors and Development\r\n
Our lab investigates:
\r\nFunctions of thyroid hormone receptors
\r\nThyroid hormone receptors (TRs) belong to the family of nuclear receptors and act as ligand-dependent transcription factors. A family of TRa and TRb receptors encoded by the related Thra and Thrb genes, respectively, have individual and interactive functions in vivo. In view of the wide range of functions of thyroid hormone (T3), it is anticipated that study of TR pathways will elucidate basic principles of receptor control of biological functions.
\r\nT3 controls many functions in development and homeostasis. Human thyroid disorders are common and result in a correspondingly wide range of disease symptoms. To understand the mechanisms of T3 action, we are investigating the underlying TR pathways, building in part upon knockout mice, deficient for one or more TRs. TRb-/- mice exhibit a hyperactive pituitary-thyroid axis and deafness. TRa1-/- mice have a low body temperature and reduced heart rate. Doubly-deficient TRa1-/-TRb-/- mice display a novel array of phenotypes not found in single TR-deficiencies including retarded growth and female infertility, establishing that TRa1 and TRb also mediate common functions in vivo.\r\n\r\n
The role of TRs in hearing: a model of genetic regulation
\r\nIn recent years, the identification of genes involved in hearing has promised to reveal the mechanisms that underlie the development and function of the auditory system. A number of genes required for hearing, including Thra and Thrb, encode transcription factors, indicating that hierarchies of transcriptional regulation play a role. Thus, the TR genes provide an excellent model for revealing how transcriptional as well as hormonal controls are integrated in this intricate sensory system.
TRb is essential for hearing whereas TRa1 is dispensable, while the deletion of all TRs exacerbates the phenotype, indicating that TRa1 makes some contribution. TRb controls the later stages of cochlear differentiation, including the maturation of the hair cells, which convert acoustic stimuli into neural responses. TRb also controls other cell types in the sensory epithelium and the formation of the tectorial membrane, a critical part of the machinery for the response to sound. Current studies suggest a model whereby a complex range of morphological and physiological events in cochlear maturation are determined by distinct TR pathways.
\r\nWe continue to investigate the molecular and cellular events involved in the cochlea. One area of study is to investigate other factors that modify TR signaling in the cochlea. Candidates include the deiodinase enzymes that metabolize thyroid hormone into active and inactive forms. These enzymes may exert powerful control over the timing of TR activity in cochlear development.\r\n
\r\nGenes involved in the late stages of cochlear differentiation
\r\nThe late stages of cochlear maturation represent a period of development that is poorly understood. Therefore, we are using TR-deficient mice as a unique model for identifying novel genes involved. A differential screen of cochlear expressed sequences has identified a major component of the cochlear basilar membrane, an extracellular matrix protein that belongs to the emilin familyof glycoproteins. This emlin-2 protein is highly enriched in the basilar membrane, a specialized elastic membrane that facilitates the precise movement of the hair cells in response to sound. We are investigating the function of this protein and other related factors in determining the unique elastic properties of the basilar membrane.
TRb2 and the development of retinal cone photoreceptors
\r\nWe previously identified a novel N-terminal variant receptor, TRb2, in the embryonic chick retina, which is located in the immature photoreceptor layer. The same receptor is present in the mouse retina and targeted mutagenesis has demonstrated that TRb2 has a fundamental role in the differentiation of the cone photoreceptors that mediate color vision. TRb2-deficient mice have cones that are sensitive to short ("blue" wavelength) light but completely lack cones that are sensitive to longer ("green") wavelengths. Thus TRb2 is unexpectedly critical for the diversification of the cone subtypes required for color vision. We are investigating the currently unknown molecular mechanisms of its action in the differentiation of cones. \r\n
Forrest D, Hanebuth E, Smeyne RJ, Everds N, Stewart CL, Wehner JM, Curran T. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor b: evidence for tissue-specific modulation of receptor function. EMBO J 1996 Jun 17; 15(12): 3006-15.
Rusch A, Erway LC, Oliver D, Vennstrom B, Forrest D. Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing. Proc Natl Acad Sci U S A 1998 Dec 22; 95(26): 15758-62.
Gothe S, Wang Z, Ng L, Kindblom JM, Campos-Barros, Ph.D. A, Ohlsson C, Vennstrom B, Forrest D. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 1999 May 15; 13(10): 1329-41.
Campos-Barros A, Amma LL, Faris JS, Shailam R, Kelley MW, Forrest D. Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing. Proc Natl Acad Sci U S A 2000 Feb 1; 97(3): 1287-92.
Rusch A, Ng L, Goodyear R, Oliver D, Lisoukov I, Vennstrom B, Richardson G, Kelley M, Forrest D. Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. J Neurosci 2001; 21: 9792-9800.
Ng L, Hurley JB, Diercks B, Srinivas M, Salto C, Vennstrom B, Reh TA, Forrest D. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genet 2001; 27: 94-98.
Forrest D, Reh TA, Rusch A. Neurodevelopmental control by thyroid hormone receptors. Curr Opin Neurobiol 2002; 12: 49-56.
Amma LL, Goodyear R, Faris JS, Jones I, Ng L, Richardson G, Forrest D. An emilin family extracellular matrix protein identified in the cochlear basilar membrane. Mol Cell Neurosci 2003; 23: 460-472.