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...

Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoRnull mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extrahematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia.

Background. Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon.Methods. We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high-resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics.Results. In the study population, the discordance rate