Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Yamaguchi, Yuki; Sawada, Jun‐ichi; Yamada, Masao; Handa, Hiroshi; Azuma, Noriyuki

doi:10.1046/j.1365-2443.1997.1170315.x

Cited by 32 publications

(38 citation statements)

References 25 publications

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“…; *P<0.05, **P<0.01, ***P<0.001. (Yamaguchi et al, 1997;Chauhan et al, 2004). Thus, in silico analysis predicts selective disruption of the DNA binding activity of the respective subdomains in the mutant proteins (supplementary material Fig.…”

Section: Leca4mentioning

confidence: 99%

“…These data imply that the multitude of effects that Pax6 exerts on patterning, neurogenesis and proliferation in the developing brain should be largely mediated by the PD. Interestingly, the PD itself is also structured in a modular, bipartite manner, with an N-terminal PAI subdomain and C-terminal RED subdomain, which can bind cooperatively or independently to their cognate sites (Epstein et al, 1994a;Yamaguchi et al, 1997). Alternative splicing of Pax6 exon 5a regulates the insertion of 14 amino acids into the PAI subdomain, thereby abolishing PAI subdomain DNA binding while retaining RED subdomain activity (Epstein et al, 1994b;Kozmik et al, 1997;Anderson et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

et al. 2013

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To achieve adequate organ development and size, cell proliferation and differentiation have to be tightly regulated and coordinated. The transcription factor Pax6 regulates patterning, neurogenesis and proliferation in forebrain development. The molecular basis of this regulation is not well understood. As the bipartite DNA-binding paired domain of Pax6 regulates forebrain development, we examined mice with point mutations in its individual DNA-binding subdomains PAI (Pax6Leca4, N50K) and RED (Pax6Leca2, R128C). This revealed distinct roles in regulating proliferation in the developing cerebral cortex, with the PAI and RED subdomain mutations reducing and increasing, respectively, the number of mitoses. Conversely, neurogenesis was affected only by the PAI subdomain mutation, phenocopying the neurogenic defects observed in full Pax6 mutants. Genome-wide expression profiling identified molecularly discrete signatures of Pax6Leca4 and Pax6Leca2 mutations. Comparison to Pax6 targets identified by chromatin immunoprecipitation led to the identification and functional characterization of distinct DNA motifs in the promoters of target genes dysregulated in the Pax6Leca2 or Pax6Leca4 mutants, further supporting the distinct regulatory functions of the DNA-binding subdomains. Thus, Pax6 achieves its key roles in the developing forebrain by utilizing particular subdomains to coordinate patterning, neurogenesis and proliferation simultaneously.

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Section: Leca4mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

et al. 2013

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“…Cooperative interactions between PAI and RED subdomains of the PD and HD were established for a number of Pax proteins (Jun and Desplan, 1996). Functional analysis of two Pax6 missense mutants, R26G and R128C, in transient reporter assays revealed that both PAI and RED subdomains of the PD could negatively regulate transactivation of both Pax6 and Pax6(5a) depending on the DNA-binding site used, P6CON or 5aCON (Yamaguchi et al, 1997). More recent studies of human PAX6 and PAX6(5a) missense mutants, including G18W, R26G, A33P, S43P, G64V, I87R, V126D and R128C, confirmed that mutations located in PAI subdomain influenced functional properties of Pax6 proteins bound to 5aCON sequences, although this site is only recognized by the RED subdomain (Chauhan et al, 2004a).…”

Section: Biochemistry Of Pax6: Binding To Dna and Transcriptional Regmentioning

confidence: 99%

Regulation of gene expression by Pax6 in ocular cells: a case of tissue-preferred expression of crystallins in lens

Cvekl¹,

Yang²,

Chauhan³

et al. 2004

Int. J. Dev. Biol.

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“…The plasmid was digested with NotI and the fragment was inserted into the NotI site of pHygEF2 to generate pHygEF2/m-cdx2. The Pax6 expression vector pCAGGS/Pax6 and pCAGGS/Pax6-5a were generous gifts from Dr Noriyuki Azuma (National Children's Hospital, Tokyo, Japan) and Dr Yuki Yamaguchi (Tokyo Institute of Technology, Yokohama, Japan) (Yamaguchi et al 1997). Expression plasmids for FLAG-tagged mouse Isl1 splicing isoforms (pHygEF2/FLAGisl1-and pHygEF2/FLAG-isl1-) have been described previously (Ando et al 2003).…”

Section: Luciferase Assaymentioning

confidence: 99%

Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells

Kataoka¹,

Shioda²,

Ando³

et al. 2004

Journal of Molecular Endocrinology

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A basic-leucine zipper transcription factor, MafA, was recently identified as one of the most important transactivators of insulin gene expression. This protein controls the glucose-regulated and pancreatic -cell-specific expression of the insulin gene through a cis-regulatory element called RIPE3b/MARE (Maf-recognition element). Here, we show that MafA expression is restricted to -cells of pancreatic islets in vivo and in insulinoma cell lines. We also demonstrate that c-Maf, another member of the Maf family of transcription factors, is expressed in islet -cells and in a glucagonoma cell line ( TC1), but not in -and -cells. An insulinoma cell line, TC6, also expressed c-Maf, albeit at a low level. Chromatin immunoprecipitation assays demonstrated that Maf proteins associate with insulin and glucagon promoters in -and -cell lines, respectively. c-Maf protein stimulated glucagon promoter activity in a transient luciferase assay, and activation of the glucagon promoter by c-Maf was more efficient than by the other -cell-enriched transcription factors, Cdx2, Pax6, and Isl-1. Furthermore, inhibition of c-Maf expression in TC1 cells by specific short hairpin RNA resulted in marked reduction of the glucagon promoter activity. Thus, c-Maf and MafA are differentially expressed in -and -cells where they regulate glucagon and insulin gene expression, respectively.

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Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Cited by 32 publications

References 25 publications

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

Functional dissection of the paired domain of Pax6 reveals molecular mechanisms of coordinating neurogenesis and proliferation

Regulation of gene expression by Pax6 in ocular cells: a case of tissue-preferred expression of crystallins in lens

Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells

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