Orphan nuclear receptors and mammalian development

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

The development of a tissue and its specialized function is often guided by control genes that encode transcription factors. During development, transcription factors can prompt immature precursor cells to form the variety of cell types that make up the mature, functional tissue. Defects in transcription factors can impair tissue function and lead to disease states. Nuclear receptors are ligand-regulated transcription factors that respond to hormones or other ligands. Orphan receptors belong to a group of nuclear receptors that lack known physiological ligands (the reason for being named “orphan” receptors) and serve critical roles in neurodevelopment. The retinoid-related orphan nuclear receptor genes Rorb and Rora are expressed in specific brain regions and sensory organs, including the eye and inner ear, and in several other tissues. It has been reported that in humans, mutations in these orphan nuclear receptor genes are associated with intellectual disability, epilepsy or other neurological impairments, implicating these genes with an important role in neurodevelopmental disease. However, the functions of these orphan receptors and how defects in these factors result in disease are poorly understood. This project aims to elucidate the functions of the Rora and Rorb genes in the development of sensory tissues for vision (the retina in the eye) and hearing (the cochlea in the inner ear) by analyses in mammalian model systems. The findings of these studies may suggest how defects in these orphan nuclear receptors cause neurodevelopmental impairment. The project themes involve neuroscience, developmental biology and molecular biology studies, and overall aims include: 1. A role for retinoid-related orphan nuclear receptors in retinal development and vision. We have investigated the function of Rorb in the retina, the light-sensitive tissue at the back of the eye that converts light into visual information using genetic model systems. Undifferentiated retinal progenitor cells generate a range of cell types including photoreceptors, interneurons and the ganglion cells that relay visual information to the brain. Cone photoreceptors mediate vision in bright light whereas rod photoreceptors mediate vision in dim light or at night. We have investigated the role of Rorb in the control of differentiation of rod and cone photoreceptors as well differentiation of horizontal and amacrine interneurons that process visual information for relaying to the optic nerve. The Rorb gene is essential for induction of a key rod-determining gene, Nrl, and also for a key interneuron-determining gene Ptf1a. We have derived a new, genetically-tagged mammalian model that allows isolation of Rorb protein for analysis of chromatin binding sites in the genome in the retina for further investigation of the control mediated by this orphan receptor in retinal differentiation. 2. The role of Rora and Rorb genes in cochlear differentiation and hearing. We are investigating a role for retinoid-related orphan nuclear receptors in cochlear development and auditory function in mammalian models. We have demonstrated differential expression patterns for both genes, suggesting several functions in the maturation of specific cell types in epithelial tissues of the cochlear duct that are required for the development of hearing. We are investigating the physiological consequences of these defects using measurements of auditory function to indicate how these genes promote the development of hearing. These findings together with previous findings (for example, in the superior colliculus, a component of the visual pathway in the brain (with Dr. Kim, Yale Univ) indicate a powerful role for retinoid-related orphan nuclear receptors in neurodevelopment and particularly in sensory systems. These studies may also offer insights relevant to tissue defects underlying some forms of neurodevelopmental disease. We are building on these findings to study the downstream target genes that are hypothesized to be regulated by these orphan receptors in differentiation in the nervous system. These investigations employ a range of genetic approaches, cell-isolation procedures and next generation sequencing, genomic analyses.