Orphan nuclear receptors and mammalian development

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

In mammalian development, the formation of a tissue and its specialized cell types is often guided by key developmental control genes. These genes prompt immature progenitor and precursor cells to form the variety of cell types that make up the fully functional organ. 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 but serve critical roles in development and cellular differentiation. The retinoid-related orphan nuclear receptor b gene (Rorb), is expressed in the retina, spinal cord, certain brain regions, sensory organs and several other tissues. Reports show that mutations in the human RORB gene are associated with intellectual disability, epilepsy and other impairments, thus implicating this gene with an important role in human disease. However, the functions of this orphan receptor gene and how defects in the gene result in disease are poorly understood. This project aims to elucidate the tissue-specific functions of Rorb in development in model systems and to reveal how dysfunction of the gene causes disease. The aims of this study are to reveal novel functions for an orphan receptor, including: 1. Function of the Rorb gene in neurodevelopment. We investigate the expression and function of Rorb in the central nervous system and sensory systems using mammalian genetic models. In the retina, undifferentiated progenitor cells generate a range of cell types including photoreceptors, interneurons and ganglion cells that relay visual information to the brain. Our studies investigate key functions for Rorb in the determination of specific retinal cell lineages, including rod and cone photoreceptors as well as horizontal and amacrine interneurons that process and relay visual information to the optic nerve. We demonstrated a key role for Rorb in the differentiation of rods, the photoreceptors that mediate vision at night or in dim light conditions. The Rorb gene is essential for induction of a key rod-determining gene, Nrl, and a key interneuron-determining gene Ptf1a. In the absence of Rorb, there is a nearly complete loss of rods and an excess of primitive cone-like cells, consistent with Rorb acting in the same pathway as Nrl. 2. The Rorb gene is also a valuable marker for cell types in other brain regions, sensory organs and a few other tissues. We are currently investigating a role for Rorb in the development of the auditory system and have investigated other functions, including in the superior colliculus, a component of the visual pathway in the brain that receives different sensory inputs and which influences head and eye movements. Collaborative studies with Dr. In-Jung Kim (Yale University) showed that the Rorb1 isoform marks specific neurons in the superficial region of the superior colliculus, which has been useful in defining these neuronal sub-types. Further collaboration with Dr David Monroe (Mayo Clinic) has revealed a role for Rorb in osteoprotection, suggesting a novel role for this gene in other tissues outside the nervous system. We are building on these findings to investigate the critical downstream target genes that we hypothesize underlie the transcriptional functions of this orphan receptor in cell differentiation and development. We address these aims using a range of genetic approaches, cell-isolation procedures and next generation sequencing analyses. We have derived a genetically-tagged Rorb model to allow the analysis of chromatin binding sites during the control of gene expression by this orphan receptor in differentiation.