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Douglas Forrest

Publications and source records attributed to Douglas Forrest.

14 recordsLinked to original sources
PubMed2006

Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina.

Most mammals have two types of cone photoreceptors, which contain either medium wavelength (M) or short wavelength (S) opsin. The number and spatial organization of cone types varies dramatically among species, presumably to fine-tune the retina for different visual environments. In the mouse, S- and M-opsin are expressed in an opposing dorsal-ventral gradient. We previously reported that cone opsin patterning requires thyroid hormone beta2, a nuclear hormone receptor that regulates transcription in conjunction with its ligand, thyroid hormone (TH). Here we show that exogenous TH inhibits S-opsin expression, but activates M-opsin expression. Binding of endogenous TH to TRbeta2 is required to inhibit S-opsin and to activate M-opsin. TH is symmetrically distributed in the retina at birth as S-opsin expression begins, but becomes elevated in the dorsal retina at the time of M-opsin onset (postnatal day 10). Our results show that TH is a critical regulator of both S-opsin and M-opsin, and suggest that a TH gradient may play a role in establishing the gradient of M-opsin. These results also suggest that the ratio and patterning of cone types may be determined by TH availability during retinal development.

Animals↗
PubMed2006

Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta.

Color vision requires the expression of opsin photopigments with different wavelength sensitivities in retinal cone photoreceptors. The basic color visual system of mammals is dichromatic, involving differential expression in the cone population of two opsins with sensitivity to short (S, blue) or medium (M, green) wavelengths. However, little is known of the factors that directly activate these opsin genes and thereby contribute to the S or M opsin identity of the cone. We report that the orphan nuclear receptor RORbeta (retinoid-related orphan receptor beta) activates the S opsin gene (Opn1sw) through binding sites upstream of the gene. RORbeta lacks a known physiological ligand and activates the Opn1sw promoter modestly alone but strongly in synergy with the retinal cone-rod homeobox factor (CRX), suggesting a cooperative means of enhancing RORbeta activity. Comparison of wild-type and mutant lacZ reporter transgenes showed that the RORbeta-binding sites in Opn1sw are required for expression in mouse retina. RORbeta-deficient mice fail to induce S opsin appropriately during postnatal cone development. Photoreceptors in these mice also lack outer segments, indicating additional functions for RORbeta in photoreceptor morphological maturation. The results identify Opn1sw as a target gene for RORbeta and suggest a key role for RORbeta in regulating opsin expression in the color visual system.

Animals↗
PubMed2005

Retinoid-related receptor (ROR) alpha mRNA expression is altered in the brain of male mice lacking all ligand-binding thyroid hormone receptor (TR) isoforms.

In the vertebrate brain, the thalamus serves as a relay and integration station for diverse neuronal information en route from the periphery to the cortex. Deficiency of TH during development results in severe cerebral abnormalities similar to those seen in the mouse when the retinoic acid receptor (ROR)alpha gene is disrupted. To investigate the effect of the thyroid hormone receptors (TRs) on RORalpha gene expression, we used intact male mice, in which the genes encoding the alpha and beta TRs have been deleted. In situ hybridization for RORalpha mRNA revealed that this gene is expressed in specific areas of the brain including the thalamus, pons, cerebellum, cortex, and hippocampus. Our quantitative data showed differences in RORalpha mRNA expression in different subthalamic nuclei between wild-type and knock-out mice. For example, the centromedial nucleus of the thalamus, which plays a role in mediating nociceptive and visceral information from the brainstem to the basal ganglia and cortical regions, has less expression of RORalpha mRNA in the knockout mice (-37%) compared to the wild-type controls. Also, in the dorsal geniculate (+72%) and lateral posterior nuclei (+58%) we found more RORalpha mRNA in dKO as compared to dWT animals. Such differences in RORalpha mRNA expression may play a role in the behavioral alterations resulting from congenital hypothyroidism.

Animals↗
PubMed2004

Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase.

The later stages of cochlear differentiation and the developmental onset of hearing require thyroid hormone. Although thyroid hormone receptors (TRs) are a prerequisite for this process, it is likely that other factors modify TR activity during cochlear development. The mouse cochlea expresses type 2 deiodinase (D2), an enzyme that converts thyroxine, the main form of thyroid hormone in the circulation, into 3,5,3'-triiodothyronine (T3) the major ligand for TRs. Here, we show that D2-deficient mice have circulating thyroid hormone levels that would normally be adequate to allow hearing to develop but they exhibit an auditory phenotype similar to that caused by systemic hypothyroidism or TR deletions. D2-deficient mice have defective auditory function, retarded differentiation of the cochlear inner sulcus and sensory epithelium, and deformity of the tectorial membrane. The similarity of this phenotype to that caused by TR deletions suggests that D2 controls the T3 signal that activates TRs in the cochlea. Thus, D2 is essential for hearing, and the results suggest that this hormone-activating enzyme confers on the cochlea the ability to stimulate its own T3 response at a critical developmental period.

Animals↗
PubMed2003

Dominant inhibition of thyroid hormone action selectively in the pituitary of thyroid hormone receptor-beta null mice abolishes the regulation of thyrotropin by thyroid hormone.

Thyroid hormones, T4 and T3, regulate their own production by feedback inhibition of TSH and TRH synthesis in the pituitary and hypothalamus when T3 binds to thyroid hormone receptors (TRs) that interact with the promoters of the genes for the TSH subunit and TRH. All TR isoforms are believed to be involved in the regulation of this endocrine axis, as evidenced by the massive dysregulation of TSH production in mice lacking all TR isoforms. However, the relative contributions of TR isoforms in the pituitary vs. the hypothalamus remain to be completely elucidated. Thus, to determine the relative contribution of pituitary expression of TR-alpha in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR-alpha function in TR-beta null mice (TR-beta-/-) by pituitary restricted expression of a dominant negative TR-beta transgene harboring a delta337T mutation. These animals exhibited 10-fold and 32-fold increase in T4 and TSH concentrations, respectively. Moreover, the negative regulation of TSH by exogenous T3 was completely absent and a paradoxical increase in TSH concentrations and TSH-beta mRNA was observed. In contrast, prepro-TRH expression levels in T3-treated TR-beta-/- were similar to levels observed in the delta337/TR-beta-/- mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-beta deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs.

Animals↗
PubMed2003

An emilin family extracellular matrix protein identified in the cochlear basilar membrane.

The precise movement of the cochlear basilar membrane (BM) stimulates the sensory hair cells during auditory transduction. However, the molecular composition of the BM that confers its specialized properties of support and elasticity is poorly understood. A differential screen of cochlear RNA from deaf mice lacking thyroid hormone receptor beta was used to identify a sequence encoding a secreted protein, which is abundant in the BM and is expressed at low levels in the heart, lung, and brain. The protein possesses several domains for protein interactions and is related to emilin (elastin microfibril interface-located protein) previously isolated from aorta. This cochlear emilin-2 mRNA is expressed in the tympanic border cells underlying the BM and an antibody detected protein in the extracellular matrix surrounding the collagenous fibers in the BM. These results identify emilin-2 as a major BM component and suggest that it contributes to the developmental assembly or function of the BM.

Amino Acid Sequence↗
PubMed2003

The thyroid hormone receptor beta gene: structure and functions in the brain and sensory systems.

Thyroid hormone profoundly influences the development of the vertebrate nervous system. The thyroid hormone receptor beta gene (Thrb) is a key mediator of many of these actions. The Thrb gene is complex, spanning up to 400 kb in mammals, and differentially expresses distinct receptor subtypes through independent tissue-specific promoters and alternative splicing. These receptors serve a range of functions in the brain as well as particularly sensitive functions in the auditory and visual sensory systems. The Thrb gene illustrates how versatility in neurodevelopmental control can be achieved at the receptor level.

Animals↗
PubMed2002

Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice.

Thiamin-responsive megaloblastic anemia syndrome (TRMA) is characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Mutations in the thiamin transporter gene SLC19A2 cause TRMA. To generate a mouse model of TRMA, we developed an Slc19a2 targeting construct using transposon-mediated mutagenesis and disrupted the gene through homologous recombination in embryonic stem cells. Erythrocytes from Slc19a2(-/-) mice lacked the high-affinity component of thiamin transport. On a thiamin-free diet, Slc19a2(-/-) mice developed diabetes mellitus with reduced insulin secretion and an enhanced response to insulin. The diabetes mellitus resolved after 6 weeks of thiamin repletion. Auditory-evoked brainstem response thresholds were markedly elevated in Slc19a2(-/-) mice on a thiamin-free diet, but were normal in wild-type mice treated on that diet as well as thiamin-fed Slc19a2(-/-) mice. Bone marrows from thiamin-deficient Slc19a2(-/-) mice were abnormal, with a megaloblastosis affecting the erythroid, myeloid and megakaryocyte lines. Thus, Slc19a2(-/-) mice have provided new insights into the TRMA disease pathogenesis and will provide a tool for studying the role of thiamin homeostasis in diabetes mellitus more broadly.

Anemia, Megaloblastic↗
PubMed2002

Neurodevelopmental control by thyroid hormone receptors.

Recent studies have provided insights into the neurodevelopmental functions of thyroid hormone signaling. The nuclear thyroid hormone receptors (TRs) are ligand-activated transcription factors and a variety of TR isotypes, generated by two genes, mediate distinct processes. In addition, deiodinase enzymes that regulate levels of the main active form of thyroid hormone, T3, are likely to cooperate closely with TRs in specifying a localized and timely response to thyroid hormones in target tissues. Some of the most sensitive processes controlled by these pathways are in the auditory and visual sensory systems.

Animals↗
PubMed2002

Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice.

T3 potently influences cholesterol metabolism through the nuclear thyroid hormone receptor beta (TRbeta), the most abundant TR isoform in rodent liver. Here, we have tested if TRalpha1, when expressed at increased levels from its normal locus, can replace TRbeta in regulation of cholesterol metabolism. By the use of TRalpha2-/-beta-/- animals that overexpress hepatic TRalpha1 6-fold, a near normalization of the total amount of T3 binding receptors was achieved. These mice are similar to TRbeta-/- and TRalpha1-/-beta-/- mice in that they fail to regulate cholesterol 7alpha-hydroxylase expression properly, and that their serum cholesterol levels are unaffected by T3. Thus, hepatic overexpression of TRalpha1 cannot substitute for absence of TRbeta, suggesting that the TRbeta gene has a unique role in T3 regulation of cholesterol metabolism in mice. However, examination of T3 regulation of hepatic target genes revealed that dependence on TRbeta is not general: T3 regulation of type I iodothyronine deiodinase and the low density lipoprotein receptor were partially rescued by TRalpha1 overexpression. These in vivo data show that TRbeta is necessary for the effects of T3 on cholesterol metabolism. That TRalpha1 only in some instances can substitute for TRbeta indicates that T3 regulation of physiological and molecular processes in the liver occurs in an isoform-specific fashion.

Animals↗