The National Institute of Diabetes & Digestive & Kidney Diseases

Thyroid hormone has numerous functions in development and physiology in vertebrate species.  In humans, thyroid hormone abnormalities in development result in pronounced mental and physical retardation.  Abnormalities in adulthood result in a range of other forms of impairment.  Using genetic approaches, we aim to elucidate the varied mechanisms that regulate where, when and how thyroid hormone acts and to uncover new functions for this hormone.

Thyroid hormone receptors belong to the nuclear receptor family and control a critical point at which the hormonal signal is converted into a cellular response.  We investigate how thyroid hormone receptors mediate specialized functions in different tissues.  We also investigate genes that cooperate with the receptor genes to determine specific responses.  An example is the activation or inactivation of the hormone by deiodinase enzymes, which may be critical determinants in certain tissues.  Ongoing studies include investigation of thyroid hormone functions in sensory systems, which have previously received little attention.

We also investigate other nuclear receptors in mammalian development, including the role of the retinoid-related orphan receptors. The study of nuclear receptors, which act as ligand-regulated transcription factors, should reveal how networks of transcriptional responses mediate specific biological processes.

1. Ng, L, Hernandez, A, He, W, Ren, T, Srinivas, M, Ma, M, Galton, VA, St.Germain, DL, Forrest, D. (2009) A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function.  Endocrinology, in press.

2. Lu, A, Ng, L, Ma, M, Kefas, B, Davies, TF, Hernandez, A, Chan, C-C, Forrest, D.  (2009) Retarded developmental expression and patterning of retinal cone opsins in hypothyroid mice.  Endocrinology, in press.

3. Liu, H., Etter, P, Hayes, S, Jones, I, Nelson, B, Hartman, B, Forrest, D, Reh, TA. (2008) NeuroD1 regulates expression of thyroid hormone receptor β2 and cone opsins in the developing mouse retina.  J. Neurosci. 28: 749 - 756.

4. Hollenberg, A, Forrest, D (2008) The Thyroid and Metabolism: The Action Continues.  Cell Metabolism 8: 10 – 12.

5. Nunez, J, Celi, F,  Ng, L, Forrest, D. (2008) Multigenic control of thyroid hormone functions in the nervous system. Mol. Cell Endocrinol. 287: 1 – 12.

6. Jones, I, Ng, L, Liu, H, Forrest, D. (2007) An intron control region differentially regulates expression of thyroid hormone receptor β2 in the cochlea, pituitary and cone photoreceptors. Mol. Endocrinol. 21: 1108 - 1119.

7. Srinivas M, Ng L, Liu H, Jia L, Forrest D  Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta.  Mol Endocrinol (20): 1728-41, 2006. [Full Text/Abstract]

8. Roberts MR, Srinivas M, Forrest D, Morreale de Escobar G, Reh TA  Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina.  Proc Natl Acad Sci U S A (103): 6218-23, 2006. [Full Text/Abstract]

9. Ng L, Goodyear RJ, Woods CA, Schneider MJ, Diamond E, Richardson GP, Kelley MW, Germain DL, Galton VA, Forrest D  Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase.  Proc Natl Acad Sci U S A (101): 3474-9, 2004. [Full Text/Abstract]

10. 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 (23): 460-72, 2003. [Full Text/Abstract]

11. Forrest D, Reh TA, Rusch A  Neurodevelopmental control by thyroid hormone receptors.  Curr Opin Neurobiol (12): 49-56, 2002. [Full Text/Abstract]

12. Ng L, Hurley JB, Dierks 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.  Nat Genet (27): 94-8, 2001. [Full Text/Abstract]

13. Rusch A, Ng L, Goodyear R, Oliver D, Lisoukov I, Vennstrom B, Richardson G, Kelley MW, Forrest D  Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors.  J Neurosci (21): 9792-800, 2001. [Full Text/Abstract]

14. Forrest D, Vennstrom B  Functions of thyroid hormone receptors in mice.  Thyroid (10): 41-52, 2000. [Full Text/Abstract]

15. Gothe S, Wang Z, Ng L, Kindblom JM, Barros AC, 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 (13): 1329-41, 1999. [Full Text/Abstract]