Essential role of POU–domain factor Brn-3c in auditory and vestibular hair cell development

Abstract

The Brn-3 subfamily of POU-domain transcription factor genes consists of three highly homologous members-Brn-3a, Brn-3b, and Brn-3c-that are expressed in sensory neurons and in a small number of brainstem nuclei. This paper describes the role of Brn-3c in auditory and vestibular system development. In the inner ear, the Brn-3c protein is found only in auditory and vestibular hair cells, and the Brn-3a and Brn-3b proteins are found only in subsets of spiral and vestibular ganglion neurons. Mice carrying a targeted deletion of the Brn-3c gene are deaf and have impaired balance. These defects ref lect a complete loss of auditory and vestibular hair cells during the late embryonic and early postnatal period and a secondary loss of spiral and vestibular ganglion neurons. Together with earlier work demonstrating a loss of trigeminal ganglion neurons and retinal ganglion cells in mice carrying targeted disruptions in the Brn-3a and Brn-3b genes, respectively, the Brn-3c phenotype reported here demonstrates that each of the Brn-3 genes plays distinctive roles in the somatosensory, visual, and auditory͞ vestibular systems.A number of transcription factors have been implicated in decisions related to neuronal vs. nonneuronal cell fate, regional specification in the nervous system, or determination of the terminally differentiated phenotype. For example, bHLH factors such as neuroD and the achaete-scute family control neural vs. ectodermal cell fates (1, 2), Hox genes control regional specification along the neuraxis (3), and several POU-domain genes act at late stages to control the survival and final differentiated phenotype of particular neuronal subtypes (4). The POU-domain family was intially defined by the mammalian pituitary-specific transcription factor Pit-1͞ GHF-1, the octamer binding proteins Oct-1 and Oct-2, and the Caenorhabditis elegans gene Unc-86 (5). Genetic studies in mice and humans indicate that many POU-domain genes function in the terminal stages of central nervous system development. SCIP͞Tst-1͞Oct-6 controls the differentiation of Schwann cells (6-8), Pit-1͞GHF-1 is required for the normal development of the anterior pituitary (9), Brn-4͞RHS2͞ POU3F4 is required for the normal development of the middle ear (10), and Brn-2 is required for the specification of subsets of neurons in the hypothalamus (11,12).The class IV POU-domain group is defined by the Unc-86 gene (13), the Drosophila I-POU gene (14,15), and the three vertebrate Brn-3 genes (16-20). The Unc-86 protein is found exclusively within a subset of neurons and neuroblasts, and Unc-86 loss-of-function mutations affect some of these cells by causing a daughter cell to assume the fate of its mother or by altering cell phenotypes postmitotically (21-23). In mammals, the three highly homologous class IV POU-domain genes, Brn-3a, Brn-3b, and Brn-3c (also referred to as Brn-3.0, Brn-3.2, and Brn-3.1, respectively), are expressed in distinct but overlapping patterns in the developing and adult brainstem, retina, and dorsal root and trigemina...

Differential Distribution of Stem Cells in the Auditory and Vestibular Organs of the Inner Ear

“…Generally, we found low or no expression of mature cell markers in all sphere populations that we investigated. For example, the hair cell markers Brn3.1, myosin VIIA, and espin (Sahly et al 1997;Xiang et al 1997;Zheng et al 2000b) were not detectable in spheres derived from the utricle and organ of Corti, but all markers were up-regulated after adherence of the spheres and 2 weeks culture under differentiation conditions. Organ of Corti-derived spheres gave rise to a population of cells that expressed the outer hair cell marker prestin (Zheng et al 2000a).…”

Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

“…Thus, the closely related POU family transcription factors Brn-3a, Brn-3b and Brn-3c were originally identified on the basis of their distinct but overlapping patterns of gene expression in the developing and adult nervous systems [3][4][5][6] and inactivation of the individual genes encoding these factors has been shown to produce defects in the development of specific parts of the nervous system. [7][8][9] However, expression of Brn-3a and Brn-3b has also been observed in nonneuronal cells notably, in the testis, 10 breast 11 and cervix. 4,12 This expression of Brn-3a in neuronal and some nonneuronal cell types is paralleled by their overexpression in tumors of neuronal and nonneuronal origin.…”

Auditory hair cell precursors immortalized from the mammalian inner ear

“…To identify hair cells in vitro, we screened epithelial cells for a number of markers. The transcription factor Brn3.1 is expressed speci¢cally in hair cells within the inner ear from about stage E14 (Ryan 1997), is essential for their di¡erentiation (Erkman et al 1996;Xiang et al 1997), and generates hearing impairments in humans when mutated (Vahava et al 1998). Hair cells subsequently express the a9 subunit of the nicotinic acetylcholine receptor (a9AChR) (Elgoyhen et al 1994;Glowatski et al 1995;Housley & Ryan 1997), a novel receptor isoform characteristic of hair cells.…”