Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors

Lee, Soo Kyung; Jurata, Linda W.; Funahashi, Junichi; Ruiz, Esmeralda C.; Pfaff, Samuel L.

doi:10.1242/dev.01179

Cited by 117 publications

(132 citation statements)

References 55 publications

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“…Neither IRX3 nor any of its vertebrate orthologues had any prior association with pancreatic development, but mouse Irx3, together with Nkx2.2, acts as a potent repressor of Hlxb9 during the development of spinal cord interneurons (26). Hlxb9 encodes a transcriptional regulator whose loss of function also affects pancreas development (27,28).…”

Section: Resultsmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

150

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Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes

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Section: Resultsmentioning

confidence: 99%

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Ragvin

Moro

Fredman

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

185

150

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“…Thus, patterning of the ventral neural tube seems to be achieved by the derepression strategy (5,24). In addition, some postmitotically expressed homeodomain transcription factors have a putative EH1 motif (24) and have been shown to repress the expression of transcription factors, which are normally expressed in other types of neurons, in specifying neuronal identity (25)(26)(27)(28)(29)(30). Thus, the derepression mechanism might also be involved in postmitotic specification events.…”

Section: The Nucleotide Sequence(s) Reported In This Paper Has Been Smentioning

confidence: 99%

Corl1, a Novel Neuronal Lineage-specific Transcriptional Corepressor for the Homeodomain Transcription Factor Lbx1

Mizuhara

Nakatani

Minaki

et al. 2005

Journal of Biological Chemistry

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During development, neuronal identity is determined by a combination of numerous transcription factors. However, the mechanisms of synergistic action of these factors in transcriptional regulation and subsequent cell fate specification are largely unknown. In this study, we identified a novel gene, Corl1, encoding a nuclear protein with homology to the Ski oncoprotein. Corl1 was highly selectively expressed in the central nervous system (CNS). In the embryonic CNS, Corl1 was expressed in a certain subset of postmitotic neurons generated posterior to the midbrain-hindbrain border. In the developing spinal cord, Corl1 was selectively expressed in the dorsal horn interneurons where a homeodomain transcription factor, Lbx1, is required for proper specification. Corl1 was localized in a nuclear dot-like structure and interacted with general transcriptional corepressors. In addition, Corl1 showed transcriptional repression activity in the GAL4-fusion system, indicating its involvement in the regulation of transcriptional repression. Furthermore, Corl1 interacted with Lbx1 and cooperatively repressed transcription, suggesting that it acts as a transcriptional corepressor for Lbx1 in regulating cell fate determination in the dorsal spinal cord. Corl1 corepressor activity did not depend on Gro/TLE activity, and Gro/TLE also functioned as a corepressor for Lbx1. Thus, Lbx1 can select two independent partners, Corl1 and Gro/TLE, as corepressors. Identification of a novel transcriptional corepressor with neuronal subtype-restricted expression might provide insights into the mechanisms of cell fate determination in neurons.Neuronal patterning is regulated by extrinsic inductive signals and downstream intrinsic signals mediated by transcription factors (1-4). In early development, neural progenitor cells are specified by secreted molecules such as sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), 1 Wnts and fibroblast growth factors, which regulate the expression pattern of downstream transcription factors including bHLH and homeodomain factors. These signals regulate sets of transcription factors at different concentration thresholds. Thus, the neural tube is regionalized into distinct progenitor domains expressing different sets of transcription factors along the anteroposterior and dorsoventral axes depending on distance from the organizing centers expressing secreted factors. As development proceeds, different classes of postmitotic neurons emerge from the individual progenitor domains during neurogenesis.Accumulating evidence has elucidated the mechanism of development in several central nervous system (CNS) regions. For example, in the ventral spinal cord, the gradient of Shh, which is secreted from the organizer regions, notochord and floor plate, is established in the ventral half of the neural tube during early development (2, 5). Graded Shh repressed expression of the class I homeodomain transcription factors, and instead induced the class II transcription factors (6). Crossinhibitory interactions between co...

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“…Outside the HD, the HB9 sequence differs from that of other known HD-containing proteins with the exception of MNR2 [Treisman et al, 1989;Draganescu et al, 1995;Wilson et al, 1996;Narlikar and Hartemink, 2006]. HB9 target genes are not known, but several regulators of Hlxb9 gene expression have been identified during MN development in other vertebrates, namely proneuronal basic helix-loop-helix (bHLH) proteins such as Ngn2, NeuroM, and LIM domain proteins such as Isl1, Lhx3, and Lhx4 [Lee and Pfaff, 2003;Lee et al, 2004;Nakano et al, 2005]. As with other HD-containing proteins, HB9 has been shown to interact with DNA sequences containing a TAAT motif, and is able to regulate its own expression when binding to the HLXB9 gene promoter TAAT motif, located in the 5 0 UTR region of the gene [Lee et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

“…HB9 target genes are not known, but several regulators of Hlxb9 gene expression have been identified during MN development in other vertebrates, namely proneuronal basic helix-loop-helix (bHLH) proteins such as Ngn2, NeuroM, and LIM domain proteins such as Isl1, Lhx3, and Lhx4 [Lee and Pfaff, 2003;Lee et al, 2004;Nakano et al, 2005]. As with other HD-containing proteins, HB9 has been shown to interact with DNA sequences containing a TAAT motif, and is able to regulate its own expression when binding to the HLXB9 gene promoter TAAT motif, located in the 5 0 UTR region of the gene [Lee et al, 2004]. Here we report on HLXB9 mutation screening in a series of 50 CS patients, 20 being familial cases and 30 being sporadic cases.…”

Section: Introductionmentioning

confidence: 99%

Spectrum ofHLXB9gene mutations in Currarino syndrome and genotype-phenotype correlation

et al. 2008

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Communicated by Sergio OttolenghiCurrarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development.

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Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors

Cited by 117 publications

References 55 publications

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX , SOX4 , and IRX3

Corl1, a Novel Neuronal Lineage-specific Transcriptional Corepressor for the Homeodomain Transcription Factor Lbx1

Spectrum ofHLXB9gene mutations in Currarino syndrome and genotype-phenotype correlation

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