The POU domain transcription factor Brn-2 is required for the determination of specific neuronal lineages in the hypothalamus of the mouse.

We generated mice carrying a loss-of-function mutation in Brn-2, a gene encoding a nervous system specific POU transcription factor, by gene targeting in embryonic stem cells. In homozygous mutant embryos, migratory precursor cells for neurons of the paraventricular nuclei (PVN) and the supraoptic nuclei (SO) of the hypothalamus die at approximately E12.5. All homozygous mutants suffered mortality within 10 days after birth, possibly because of a complete deficiency of these neurons in the hypothalamus. Although neither developmental nor histological abnormalities were observed in heterozygous mice, the levels of expression of vasopressin and oxytocin in the hypothalamus of these animals were half these of wild-type mice. These results strongly suggest that Brn-2 plays an essential role in the determination and development of the PVN and SO neuronal lineages in the hypothalamus.

[1]  C. Auffray,et al.  Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. , 2005, European journal of biochemistry.

[2]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[3]  L. Swanson,et al.  Model of forebrain regionalization based on spatiotemporal patterns of POU‐III homeobox gene expression, birthdates, and morphological features , 1995, The Journal of comparative neurology.

[4]  J. Newell,et al.  OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins , 1995, Cell.

[5]  L. Muglia,et al.  Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need , 1995, Nature.

[6]  H. Hamada,et al.  A CNS-specific POU transcription factor, Brn-2, is required for establishing mammalian neural cell lineages , 1993, Neuron.

[7]  J. Manfredi,et al.  Spacing and orientation of bipartite DNA-binding motifs as potential functional determinants for POU domain factors. , 1993, Genes & development.

[8]  Y. Fukui,et al.  Reciprocal synaptic relations between CRF-immunoreactive- and TRH-immunoreactive neurons in the paraventricular nucleus of the rat hypothalamus , 1993, Brain Research.

[9]  M. Wegner,et al.  POU-domain proteins: structure and function of developmental regulators. , 1993, Current opinion in cell biology.

[10]  M. Rosenfeld,et al.  Pit-1-dependent expression of the receptor for growth hormone releasing factor mediates pituitary cell growth , 1992, Nature.

[11]  M. Rudnicki,et al.  Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development , 1992, Cell.

[12]  M. Rosenfeld,et al.  Anterior pituitary development: Short tales from dwarf mice , 1992, Cell.

[13]  F. Wondisford,et al.  A Mutation in the POU-Homeodomain of Pit-1 Responsible for Combined Pituitary Hormone Deficiency , 1992, Science.

[14]  M. Rosenfeld,et al.  Brain 4: a novel mammalian POU domain transcription factor exhibiting restricted brain‐specific expression. , 1992, The EMBO journal.

[15]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[16]  M. Nirenberg,et al.  Structure and evolution of four POU domain genes expressed in mouse brain. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  H. Niwa,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector. , 1991, Gene.

[18]  M. Rudnicki,et al.  Simplified mammalian DNA isolation procedure. , 1991, Nucleic acids research.

[19]  Larry W. Swanson,et al.  Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1 , 1990, Nature.

[20]  J. Battey,et al.  Structure of mouse vasopressin and oxytocin genes. , 1990, Brain research. Molecular brain research.

[21]  M. Rosenfeld,et al.  The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1—Pit-1 interactions , 1990, Cell.

[22]  K. Okamoto,et al.  A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells , 1990, Cell.

[23]  H. Schöler,et al.  A family of octamer‐specific proteins present during mouse embryogenesis: evidence for germline‐specific expression of an Oct factor. , 1989, The EMBO journal.

[24]  W. Schaffner,et al.  Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. , 1989, Nucleic acids research.

[25]  L. Swanson,et al.  Expression of a large family of POU-domain regulatory genes in mammalian brain development , 1989, Nature.

[26]  W. Schaffner,et al.  A cloned octamer transcription factor stimulates transcription from lymphoid–specific promoters in non–B cells , 1988, Nature.

[27]  W. Herr,et al.  The POU domain is a bipartite DNA-binding structure , 1988, Nature.

[28]  H. Horvitz,et al.  The C. elegans cell lineage and differentiation gene unc-86 encodes a protein with a homeodomain and extended similarity to transcription factors , 1988, Cell.

[29]  W. Herr,et al.  The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. , 1988, Genes & development.

[30]  M. Rosenfeld,et al.  A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype , 1988, Cell.

[31]  T. Deerinck,et al.  The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein , 1988, Cell.

[32]  P. Sharp,et al.  Cloning of a lymphoid-specific cDNA encoding a protein binding the regulatory octamer DNA motif. , 1988, Science.

[33]  M. Rosenfeld,et al.  Activation of cell-specific expression of rat growth hormone and prolactin genes by a common transcription factor. , 1988, Science.

[34]  R. Kuwano,et al.  Molecular Cloning of cDNA to mRNA for a Cerebellar Spot 35 Protein , 1987, Journal of neurochemistry.

[35]  J. Battey,et al.  The human vasopressin gene is linked to the oxytocin gene and is selectively expressed in a cultured lung cancer cell line. , 1985, The Journal of biological chemistry.

[36]  S. Hisano,et al.  Freeze-drying technique in electron microscopic immunohistochemistry. , 1985, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[37]  D. Richter,et al.  Single base deletion in the vasopressin gene is the cause of diabetes insipidus in Brattleboro rats , 1984, Nature.

[38]  T. Iwanaga,et al.  Isolation and immunohistochemical localization of a cerebellar protein , 1984, Neuroscience Letters.

[39]  R. Ivell,et al.  Structure and comparison of the oxytocin and vasopressin genes from rat. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Rich,et al.  Vasopressin and oxytocin mRNA regulation in the rat assessed by hybridization with synthetic oligonucleotides. , 1983, The Journal of biological chemistry.

[41]  H. Okamura,et al.  Time of vasopressin neuron origin in the mouse hypothalamus: examination by combined technique of immunocytochemistry and [3H]thymidine autoradiography. , 1983, Brain research.

[42]  H. Kawano,et al.  Immunohistochemical studies of intrahypothalamic somatostatin-containing neurons in rat , 1982, Brain Research.

[43]  S. Seif,et al.  Neurohypophyseal peptides in the developing rat fetus , 1980, Brain Research.

[44]  J. Sloper,et al.  Histogenesis of the supraoptic and paraventricular neurosecretory cells of the mouse hypothalamus. , 1980, Journal of anatomy.

[45]  M. Capecchi,et al.  Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. , 1993, Development.

[46]  M. Rosenfeld,et al.  Expression of a family of POU-domain protein regulatory genes during development of the central nervous system. , 1992, Annual review of neuroscience.

[47]  H. V. Van Tol,et al.  Oxytocin gene expression in discrete hypothalamic magnocellular cell groups is stimulated by prolonged salt loading. , 1987, Endocrinology.