Mapping activation and repression domains of the vnd/NK-2 homeodomain protein

Степченко, А. Г.; Nirenberg, Marshall W.

doi:10.1073/pnas.0404775101

Cited by 18 publications

(25 citation statements)

References 46 publications

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“…Glutamine-or proline-rich or acidic regions are known to serve as transcriptional activation domains (30). The C-terminal end of BSX1A contains a number of acidic residues (Glu and Asp), including a cluster, (2,6,10,21,24,25,27,29).…”

Section: Discussionmentioning

confidence: 99%

Cloning and Functional Analysis of Hypothalamic Homeobox Gene Bsx1a and Its Isoform, Bsx1b

Chu

Ohtoshi

2007

Molecular and Cellular Biology

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The hypothalamus is a key regulatory unit of the neuroendocrine system and plays an essential role in energy balance and reproduction. Despite its important role, the molecular mechanisms underlying hypothalamic development are not fully understood. Here, we report molecular analyses of a newly identified murine homeobox gene, Bsx/Bsx1a, that is expressed in the developing and postnatal hypothalamus. We demonstrate that BSX1A is a DNA binding protein and a transcriptional activator. Transcriptional reporter assays identified the C-terminal region of BSX1A as an activation domain. We have isolated an alternative splice form of Bsx1a, designated Bsx1b, which retains the N-terminal region but lacks the homeodomain. Analyses of subcellular localization using transfected cell lines revealed that BSX1A and BSX1B localize in the nuclei and cytoplasm, respectively. Immunohistochemical analyses suggested that both BSX1A and BSX1B are expressed in the neonatal hypothalamus. Taking these data together, we propose that alternative RNA splicing is involved in hypothalamic development/function.The hypothalamus-pituitary axis is a major component of the neuroendocrine system that controls the homeostasis of energy balance and reproduction. Disturbances of hypothalamic functions cause a variety of human health problems that include growth retardation, obesity, infertility, and hormoneregulated tumor progression. Much has been elucidated in the development of the pituitary in terms of transcriptional regulation; however, relatively little is known about the development of hypothalamic neurons (4,5,16,28,31,35).Although the hypothalamus consists of several cell types located in different regions, only a few transcription factors have been identified that are expressed in the developing hypothalamus. Brn-2 encodes a POU domain transcription factor, and its targeted mutation results in the loss of corticotropin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) in Brn-2-expressing cells. The homozygous mutant mice die in the neonatal period with a decrease in size and weight (18,26). The basic helix-loop-helix (bHLH)-Per-ArntSim transcription factor Sim1 is expressed in the paraventricular, the supraoptic, and the anterior periventricular nuclei. In Sim1 homozygous mutant mice, OT-, AVP-, thyrotropin-releasing hormone-, CRH-, and somatostatin (SS)-secreting neurons are absent in the Sim1-expressing regions (15). The Sim1 mutant mice die within 24 h after birth. Thus, the phenotype of Sim1 mutant mice overlaps with but is more severe than that of Brn-2 mutant mice. The Sim1 mutant hypothalamus fails to express Brn-2 during development, suggesting that a part of the phenotype of Sim1 mutant mice is due to loss of Brn-2 and that BRN-2 acts downstream of SIM1. Another bHLH-Per-ArntSim transcription factor, Arnt-2, is also involved in hypothalamic development. Arnt-2 mutant mice show a strikingly similar phenotype to the Sim1-deficient mice, consistent with the finding that SIM1 and ARNT-2 form a heterodimer complex in vivo (...

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Section: Discussionmentioning

confidence: 99%

Cloning and Functional Analysis of Hypothalamic Homeobox Gene Bsx1a and Its Isoform, Bsx1b

Chu

Ohtoshi

2007

Molecular and Cellular Biology

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“…4). As FOZI-1 contains a Q-rich region and two C 2 H 2 zinc finger motifs that are characteristic of transcription factors (Matsuzaki et al, 1995;Iuchi, 2001;Stepchenko and Nirenberg, 2004), we propose that FOZI-1 acts as a transcription factor required for proper fate specification in the M lineage.…”

Section: Discussionmentioning

confidence: 99%

“…3B): a glutaminerich region (residues 88-133), two C 2 H 2 zinc finger motifs (residues 177-201) and an FH2 formin homology domain (residues 369-732). The glutamine-rich region and the zinc finger motifs are characteristics of transcription factors (Matsuzaki et al, 1995;Iuchi, 2001;Stepchenko and Nirenberg, 2004). The FH2 domain is conserved among a large family of proteins called formins, which are present in a range of organisms, from yeast to humans (Higgs and Peterson, 2005).…”

Section: Fozi-1 Encodes a Novel Formin With Two C 2 H 2 Zn Fingers Anmentioning

confidence: 99%

A Zn-finger/FH2-domain containing protein, FOZI-1, acts redundantly with CeMyoD to specify striated body wall muscle fates in theCaenorhabditis eleganspostembryonic mesoderm

Amin

Pruyne

et al. 2007

Development

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Striated muscle development in vertebrates requires the redundant functions of multiple members of the MyoD family. Invertebrates such as Drosophila and Caenorhabditis elegans contain only one MyoD homolog in each organism. Earlier observations suggest that factors outside of the MyoD family might function redundantly with MyoD in striated muscle fate specification in these organisms. However, the identity of these factors has remained elusive. Here, we describe the identification and characterization of FOZI-1, a putative transcription factor that functions redundantly with CeMyoD (HLH-1) in striated body wall muscle (BWM) fate specification in the C. elegans postembryonic mesoderm. fozi-1 encodes a novel nuclear-localized protein with motifs characteristic of both transcription factors and actin-binding proteins. We show that FOZI-1 shares the same expression pattern as CeMyoD in the postembryonic mesodermal lineage, the M lineage, and that fozi-1-null mutants exhibit similar M lineage-null defects to those found in animals lacking CeMyoD in the M lineage (e.g. loss of a fraction of M lineage-derived BWMs). Interestingly, fozi-1-null mutants with a reduced level of CeMyoD lack most, if not all, M lineage-derived BWMs. Our results indicate that FOZI-1 and the Hox factor MAB-5 function redundantly with CeMyoD in the specification of the striated BWM fate in the C. elegans postembryonic mesoderm, implicating a remarkable level of complexity for the production of a simple striated musculature in C. elegans.

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“…These interactions 3943 RESEARCH ARTICLE DV genetic network in brain patterning help to refine the pattern into mutually exclusive domains at the onset of neurogenesis, which is important as both genes provide positional information that subsequently specifies the identity of individual brain NBs (Urbach and Technau, 2003b). Depending on the context, Vnd/Nkx2 can act as a transcriptional activator or repressor, as determined by physical interaction with the corepressor Groucho, which enhances repression (Chu et al, 1998;Cowden and Levine, 2003;Muhr et al, 2001;McDonald et al, 1998;Stepchenko and Nierenberg. 2004;Uhler et al, 2007;Yu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Ems and Nkx6 are central regulators in dorsoventral patterning of the Drosophila brain

2009

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In central nervous system development, the identity of neural stem cells (neuroblasts) critically depends on the precise spatial patterning of the neuroectoderm in the dorsoventral (DV) axis. Here, we uncover a novel gene regulatory network underlying DV patterning in the Drosophila brain, and show that the cephalic gap gene empty spiracles (ems) and the Nk6 homeobox gene (Nkx6) encode key regulators. The regulatory network implicates novel interactions between these and the evolutionarily conserved homeobox genes ventral nervous system defective (vnd), intermediate neuroblasts defective (ind) and muscle segment homeobox (msh). We show that Msh cross-repressively interacts with Nkx6 to sustain the boundary between dorsal and intermediate neuroectoderm in the tritocerebrum (TC) and deutocerebrum (DC), and that Vnd positively regulates Nkx6 by suppressing Msh. Remarkably, Ems is required to activate Nkx6, ind and msh in the TC and DC, whereas later Nkx6 and Ind act together to repress ems in the intermediate DC. Furthermore, the initially overlapping expression of Ems and Vnd in the ventral/intermediate TC and DC resolves into complementary expression patterns due to cross-repressive interaction. These results indicate that the anteroposterior patterning gene ems controls the expression of DV genes, and vice versa. In addition, in contrast to regulation in the ventral nerve cord, cross-inhibition between homeodomain factors (between Ems and Vnd, and between Nkx6 and Msh) is essential for the establishment and maintenance of discrete DV gene expression domains in the Drosophila brain. This resembles the mutually repressive relationship between pairs of homeodomain proteins that pattern the vertebrate neural tube in the DV axis.KEY WORDS: Brain development, Neuroectodermal regionalization, Stem cell specification, Drosophila, ems/Emx, Nkx6 (HGTX), vnd/Nkx2, msh (Drop)/Msx, ind/Gsx

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Mapping activation and repression domains of the vnd/NK-2 homeodomain protein

Cited by 18 publications

References 46 publications

Cloning and Functional Analysis of Hypothalamic Homeobox Gene Bsx1a and Its Isoform, Bsx1b

Cloning and Functional Analysis of Hypothalamic Homeobox Gene Bsx1a and Its Isoform, Bsx1b

A Zn-finger/FH2-domain containing protein, FOZI-1, acts redundantly with CeMyoD to specify striated body wall muscle fates in theCaenorhabditis eleganspostembryonic mesoderm

Ems and Nkx6 are central regulators in dorsoventral patterning of the Drosophila brain

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