Genomes and Genes
Gene Symbol: Nkx6-1
Description: NK6 homeobox 1
Alias: NKX6A, Nkx6.1, homeobox protein Nkx-6.1, Drosophila NK transcription factor related, gene family 6, locus 1, NK6 transcription factor related, locus 1, homeobox protein NK-6 homolog A, homeodomain transcription factor Nkx6.1
- Pedersen J, Nelson S, Jorgensen M, Henseleit K, Fujitani Y, Wright C, et al. Endodermal expression of Nkx6 genes depends differentially on Pdx1. Dev Biol. 2005;288:487-501 pubmed..2 or Nkx6.3 expression in anterior chicken endoderm. These results demonstrate that Nkx6.1 lies downstream of Pdx1 in a genetic pathway and that Pdx1 is required and sufficient for Nkx6.1 expression in the early foregut endoderm. ..
- Wijgerde M, McMahon J, Rule M, McMahon A. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev. 2002;16:2849-64 pubmed..Thus, Hh signaling is essential for organizing ventral cell pattern, possibly through the control of differential cell affinities. ..
- Nishimura W, Kondo T, Salameh T, El Khattabi I, Dodge R, Bonner Weir S, et al. A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. Dev Biol. 2006;293:526-39 pubmed..Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth. ..
- Chamberlain C, Jeong J, Guo C, Allen B, McMahon A. Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development. 2008;135:1097-106 pubmed publisher..This study, in which we directly observe, measure, localize and modify notochord-derived Shh ligand in the context of neural patterning, provides several new insights into mechanisms of Shh morphogen action...
- Götz K, Briscoe J, Ruther U. Homozygous Ft embryos are affected in floor plate maintenance and ventral neural tube patterning. Dev Dyn. 2005;233:623-30 pubmed
- Ferri A, Lin W, Mavromatakis Y, Wang J, Sasaki H, Whitsett J, et al. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 2007;134:2761-9 pubmed..Altogether, our results demonstrate that Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. ..
- Bai C, Stephen D, Joyner A. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell. 2004;6:103-15 pubmed..Therefore, in the spinal cord all Hh signaling is Gli dependent. Furthermore, a combination of Gli2 and Gli3 is required to regulate motor neuron development and spatial patterning of ventral spinal cord progenitors. ..
- Sussel L, Kalamaras J, Hartigan O Connor D, Meneses J, Pedersen R, Rubenstein J, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development. 1998;125:2213-21 pubmed..1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state. ..
- Wang J, Elghazi L, Parker S, Kizilocak H, Asano M, Sussel L, et al. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation. Dev Biol. 2004;266:178-89 pubmed..This role of Pax4 appears to be accomplished via its genetic interaction with another homeobox gene, Nkx2.2. ..
- Schaffer A, Taylor B, Benthuysen J, Liu J, Thorel F, Yuan W, et al. Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet. 2013;9:e1003274 pubmed publisher..Given the lack of Nkx6.1 expression and aberrant activation of non-beta endocrine hormones in human embryonic stem cell (hESC)-derived insulin(+) cells, our study has significant implications for developing cell replacement therapies. ..
- Perez Balaguer A, Puelles E, Wurst W, Martinez S. Shh dependent and independent maintenance of basal midbrain. Mech Dev. 2009;126:301-13 pubmed publisher..Based on our results and recently published data, we suggest the existence of a specific genetic pathway for the specification of the mesencephalic red nucleus. Foxa2 could be the candidate gene that might control this genetic pathway. ..
- Prado C, Pugh Bernard A, Elghazi L, Sosa Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci U S A. 2004;101:2924-9 pubmed..2 and Pax4 are required to specify or maintain differentiation of the beta cell fate. This finding also suggests that there is a genetic component underlying the balance between insulin and ghrelin in regulating glucose metabolism. ..
- Du A, Hunter C, Murray J, Noble D, Cai C, Evans S, et al. Islet-1 is required for the maturation, proliferation, and survival of the endocrine pancreas. Diabetes. 2009;58:2059-69 pubmed publisher..These results demonstrate the requirement for Isl-1 in the maturation, proliferation, and survival of the second wave of hormone-producing islet cells. ..
- Tran P, Haycraft C, Besschetnova T, Turbe Doan A, Stottmann R, Herron B, et al. THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet. 2008;40:403-410 pubmed publisher..Specifically, the aln mutation uncouples the roles of anterograde and retrograde transport in SHH signaling, suggesting that anterograde IFT is required for GLI activation and that retrograde IFT modulates this event. ..
- Heiser P, Lau J, Taketo M, Herrera P, Hebrok M. Stabilization of beta-catenin impacts pancreas growth. Development. 2006;133:2023-32 pubmed..Taken together, these data suggest a previously unappreciated temporal/spatial role for beta-catenin signaling in the regulation of pancreas organ growth. ..
- Oster A, Jensen J, Edlund H, Larsson L. Homeobox gene product Nkx 6.1 immunoreactivity in nuclei of endocrine cells of rat and mouse stomach. J Histochem Cytochem. 1998;46:717-21 pubmed..1-positive nuclei. Our data show that Pdx-1 is needed for Nkx 6.1 expression and suggest a role for Nkx 6.1 in the maturation of gastrin- and serotonin-positive precursor cells...
- Kilic G, Wang J, Sosa Pineda B. Osteopontin is a novel marker of pancreatic ductal tissues and of undifferentiated pancreatic precursors in mice. Dev Dyn. 2006;235:1659-67 pubmed..Finally, the maintenance of Opn expression in pancreatic tissues of adults argues for a possible function of this protein in injury and pathologic responses. ..
- Cai J, Qi Y, Hu X, Tan M, Liu Z, Zhang J, et al. Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of Nkx6 regulation and Shh signaling. Neuron. 2005;45:41-53 pubmed..In addition, we provide genetic evidence that oligodendrogenesis can occur in the absence of hedgehog receptor Smoothened, which is essential for all hedgehog signaling. ..
- Omodei D, Acampora D, Mancuso P, Prakash N, Di Giovannantonio L, Wurst W, et al. Anterior-posterior graded response to Otx2 controls proliferation and differentiation of dopaminergic progenitors in the ventral mesencephalon. Development. 2008;135:3459-70 pubmed publisher..Thus, our data provide new insights into the mechanism of mesDA neuron specification and suggest Otx2 as a potential target for cell replacement-based therapeutic approaches in PD. ..
- Lu Q, Sun T, Zhu Z, Ma N, Garcia M, Stiles C, et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell. 2002;109:75-86 pubmed..Neither Olig gene is required for astrocytes. These findings, together with fate mapping analysis of Olig-expressing cells, indicate that oligodendrocytes are derived from Olig-specified progenitors that give rise also to neurons. ..
- Henseleit K, Nelson S, Kuhlbrodt K, Hennings J, Ericson J, Sander M. NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas. Development. 2005;132:3139-49 pubmed..We demonstrate that expression of Myt1 depends on overall Nkx6 gene dose, and therefore identify Myt1 as a possible downstream target of Nkx6 genes in the endocrine differentiation pathway. ..
- Ono Y, Nakatani T, Sakamoto Y, Mizuhara E, Minaki Y, Kumai M, et al. Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development. 2007;134:3213-25 pubmed..Our data provide insights into the mechanisms of specification and generation of mesDA neurons, and illustrate a useful cell replacement approach for Parkinson's disease. ..
- Briscoe J, Sussel L, Serup P, HARTIGAN O CONNOR D, Jessell T, Rubenstein J, et al. Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling. Nature. 1999;398:622-7 pubmed..Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity. ..
- Tang M, Villaescusa J, Luo S, Guitarte C, Lei S, Miyamoto Y, et al. Interactions of Wnt/beta-catenin signaling and sonic hedgehog regulate the neurogenesis of ventral midbrain dopamine neurons. J Neurosci. 2010;30:9280-91 pubmed publisher..Persistent activation of beta-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of beta-catenin in midline progenitors promotes the generation of dopamine neurons. ..
- Du A, McCracken K, Walp E, Terry N, Klein T, Han A, et al. Arx is required for normal enteroendocrine cell development in mice and humans. Dev Biol. 2012;365:175-88 pubmed publisher..Taken together, our findings uncover a novel and conserved role of Arx in mammalian endocrine cell development and provide a potential cause for the chronic diarrhea seen in both humans and mice carrying Arx mutations. ..
- Yang Y, Thorel F, Boyer D, Herrera P, Wright C. Context-specific ?- to-?-cell reprogramming by forced Pdx1 expression. Genes Dev. 2011;25:1680-5 pubmed publisher..Our findings reveal that Pdx1 can work single-handedly as a potent context-dependent autonomous reprogramming agent, and suggest a postnatal differentiation evaluation stage involved in normal endocrine maturation. ..
- Yamanaka Y, Tamplin O, Beckers A, Gossler A, Rossant J. Live imaging and genetic analysis of mouse notochord formation reveals regional morphogenetic mechanisms. Dev Cell. 2007;13:884-96 pubmed..Therefore, we propose three distinct regions within the mouse notochord, each with unique morphogenetic origins...
- Persson M, Stamataki D, te Welscher P, Andersson E, Böse J, Ruther U, et al. Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev. 2002;16:2865-78 pubmed..Together these data raise the possibility that Gli proteins act as common mediators integrating Shh signals, and other sources of positional information, to control patterning throughout the ventral neural tube. ..
- Weatherbee S, Niswander L, Anderson K. A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. Hum Mol Genet. 2009;18:4565-75 pubmed publisher..Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1...
- Schwitzgebel V, Scheel D, Conners J, Kalamaras J, Lee J, Anderson D, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development. 2000;127:3533-42 pubmed
- Thompson N, Gesina E, Scheinert P, Bucher P, Grapin Botton A. RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors. Mol Cell Biol. 2012;32:1189-99 pubmed publisher..In addition, we identify Bmp7, Nr5a2, RhoV, and P2rx1 as new targets of PTF1a in pancreas progenitors. ..
- Joksimovic M, Anderegg A, Roy A, Campochiaro L, Yun B, Kittappa R, et al. Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools. Proc Natl Acad Sci U S A. 2009;106:19185-90 pubmed publisher..This refined ontogenetic definition will expand understanding of dopamine neuron biology and selective susceptibility, and will impact stem cell-derived therapies and models for PD. ..
- Norgaard G, Jensen J, Jensen J. FGF10 signaling maintains the pancreatic progenitor cell state revealing a novel role of Notch in organ development. Dev Biol. 2003;264:323-38 pubmed..These data suggest that FGF10 signaling serves to integrate cell growth and terminal differentiation at the level of Notch activation, revealing a novel second role of this key signaling system during pancreatic development. ..
- Sugimori M, Nagao M, Bertrand N, Parras C, Guillemot F, Nakafuku M. Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development. 2007;134:1617-29 pubmed..We propose a molecular code model whereby the combinatorial actions of two classes of transcription factors coordinately regulate the domain-specific temporal sequence of neurogenesis and gliogenesis in the developing spinal cord. ..
- Liu J, Heydeck W, Zeng H, Liu A. Dual function of suppressor of fused in Hh pathway activation and mouse spinal cord patterning. Dev Biol. 2012;362:141-53 pubmed publisher..Finally, by altering the level of Gli3 repressor on a background of reduced Gli activator activities, we reveal an important contribution of Gli3 repressor activity to the Hh pathway activation and the D/V patterning of the spinal cord. ..
- Collombat P, Mansouri A, Hecksher Sorensen J, Serup P, Krull J, Gradwohl G, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes Dev. 2003;17:2591-603 pubmed..We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts. ..
- Seymour P, Freude K, Tran M, Mayes E, Jensen J, Kist R, et al. SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci U S A. 2007;104:1865-70 pubmed..These findings will be of major significance for the development of in vitro protocols for cell replacement therapies. ..
- CHAO C, Loomis Z, Lee J, Sussel L. Genetic identification of a novel NeuroD1 function in the early differentiation of islet alpha, PP and epsilon cells. Dev Biol. 2007;312:523-32 pubmed..Furthermore, this study reveals a previously unappreciated early function of NeuroD1 in regulating the specification of alpha, PP and epsilon cells. ..
- Harmon E, Apelqvist A, Smart N, Gu X, Osborne D, Kim S. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development. 2004;131:6163-74 pubmed..Thus, our studies reveal mechanisms by which GDF11 regulates the production and maturation of islet progenitor cells in pancreas development. ..
- Wong R, Wlodarczyk B, Min K, Scott M, Kartiko S, Yu W, et al. Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube. Hum Mol Genet. 2008;17:587-601 pubmed..The mutant Fkbp8 allele is a new experimental model which will be useful in dissecting the pathogenesis of spinal NTDs, and enhance our understanding of the etiology of human NTDs...
- Jensen J, Heller R, Funder Nielsen T, Pedersen E, Lindsell C, Weinmaster G, et al. Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes. 2000;49:163-76 pubmed..Dynamic expression of Notch1 in PDX+ epithelial cells suggests that Notch signaling could inhibit a Ngn-NeuroD cascade as seen in the nervous system and thus prevent premature differentiation of endocrine cells. ..
- Liu R, Cai J, Hu X, Tan M, Qi Y, German M, et al. Region-specific and stage-dependent regulation of Olig gene expression and oligodendrogenesis by Nkx6.1 homeodomain transcription factor. Development. 2003;130:6221-31 pubmed..In the hindbrain, unlike in the spinal cord, Olig1 and Olig2 can be expressed both inside and outside the Nkx6.1-expressing domains and oligodendrogenesis in this region is not dependent on Nkx6.1 activity. ..
- Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development. 2000;127:5533-40 pubmed..Together, these experiments reveal two independently controlled pathways for beta-cell differentiation, and place Nkx6.1 downstream of Nkx2.2 in the major pathway of beta-cell differentiation. ..
- Mastracci T, Wilcox C, Arnés L, Panea C, Golden J, MAY C, et al. Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression. Dev Biol. 2011;359:1-11 pubmed publisher..Together, these experiments identify novel genetic interactions between Nkx2.2 and Arx within the endocrine progenitor cells that ensure the correct specification and regulation of endocrine hormone-producing cells. ..
- Seymour P, Freude K, Dubois C, Shih H, Patel N, Sander M. A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation. Dev Biol. 2008;323:19-30 pubmed publisher..Our findings therefore suggest that defective endocrine specification might underlie the pancreatic phenotype of individuals with CD. ..
- Wang C, Pan Y, Wang B. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors. Development. 2010;137:2001-9 pubmed publisher..Our study provides a new insight into the regulation of Gli2 and Gli3 stability and processing by Sufu and Spop, and reveals the unexpected Sufu-independent Gli3 repressor function...
- Schaffer A, Freude K, Nelson S, Sander M. Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. Dev Cell. 2010;18:1022-9 pubmed publisher..Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development. ..
- Tang M, Miyamoto Y, Huang E. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons. Development. 2009;136:2027-38 pubmed publisher..They also suggest that beta-catenin-mediated signaling pathways can be targeted to promote and expand DA neurons in cell-based therapeutic strategies. ..
- Waite M, Skidmore J, Billi A, Martin J, Martin D. GABAergic and glutamatergic identities of developing midbrain Pitx2 neurons. Dev Dyn. 2011;240:333-46 pubmed publisher..Our data suggest that PITX2 is present in regionally restricted subpopulations of midbrain neurons and may have unique functions that promote GABAergic and glutamatergic differentiation. ..
- Artner I, Blanchi B, Raum J, Guo M, Kaneko T, Cordes S, et al. MafB is required for islet beta cell maturation. Proc Natl Acad Sci U S A. 2007;104:3853-8 pubmed..These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells. ..
- Heller R, Stoffers D, Liu A, Schedl A, Crenshaw E, Madsen O, et al. The role of Brn4/Pou3f4 and Pax6 in forming the pancreatic glucagon cell identity. Dev Biol. 2004;268:123-34 pubmed..2 cells. The pancreatic phenotype of the pax6 mutants can be rescued with a YAC clone containing the human Pax6 gene. ..
- Jeong J, McMahon A. Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1. Development. 2005;132:143-54 pubmed..Furthermore, this feedback mechanism is crucial in generating a neural tube that contains appropriate numbers of all ventral and intermediate neuronal cell types. ..
- Doyle M, Loomis Z, Sussel L. Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. Development. 2007;134:515-23 pubmed..2 through its TN domain. These studies suggest that Nkx2.2 functions predominantly as a transcriptional repressor during specification of endocrine cell types in the pancreas. ..
- Vallstedt A, Muhr J, Pattyn A, Pierani A, Mendelsohn M, Sander M, et al. Different levels of repressor activity assign redundant and specific roles to Nkx6 genes in motor neuron and interneuron specification. Neuron. 2001;31:743-55 pubmed
- Briscoe J, Pierani A, Jessell T, Ericson J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell. 2000;101:435-45 pubmed..The combinatorial expression of three of these proteins--Nkx6.1, Nkx2.2, and Irx3--specifies the identity of three classes of neurons generated in the ventral third of the neural tube. ..
- Novitch B, Chen A, Jessell T. Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron. 2001;31:773-89 pubmed..Together, these studies show that Olig2 has a critical role in integrating diverse features of motor neuron differentiation in the developing spinal cord. ..
- Magenheim J, Ilovich O, Lazarus A, Klochendler A, Ziv O, Werman R, et al. Blood vessels restrain pancreas branching, differentiation and growth. Development. 2011;138:4743-52 pubmed publisher..The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus, the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells. ..
- Taylor B, Liu F, Sander M. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Rep. 2013;4:1262-75 pubmed publisher..Given that Nkx6.1 levels are reduced in human type 2 diabetic beta cells, our study lends support to the concept that loss of beta cell features could contribute to the pathogenesis of diabetes. ..
- Peltopuro P, Kala K, Partanen J. Distinct requirements for Ascl1 in subpopulations of midbrain GABAergic neurons. Dev Biol. 2010;343:63-70 pubmed publisher..Also, our results have implications on understanding the origins of the various midbrain GABAergic neuron groups in the embryonic neuroepithelium. ..
- Cheung H, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V, et al. The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal. 2009;2:ra29 pubmed publisher..Thus, Kif7 is a missing component of the mammalian Hh signaling machinery, implying a greater commonality between the Drosophila and mammalian system than the prevailing view suggests. ..
- Nakatani T, Minaki Y, Kumai M, Ono Y. Helt determines GABAergic over glutamatergic neuronal fate by repressing Ngn genes in the developing mesencephalon. Development. 2007;134:2783-93 pubmed