Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog

Motoyama, Jun; Tsuruo, Takashi; Takeshima, Kazuhito; Hui, Chi‐chung

doi:10.1038/ng0298-104

Cited by 197 publications

(134 citation statements)

References 19 publications

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“…The PTCH mammalian paralogues, PTCH1 and PTCH2, have a high amino acid sequence identity (57%) (Carpenter et al, 1998;Smyth et al, 1999;Zaphiropoulos et al, 1999), are target genes of HH signaling (Motoyama et al, 1998;Rahnama et al, 2004), and are biochemically similar in their binding affinities with SHH, DHH, IHH and SMO (Carpenter et al, 1998). However, PTCH2 cannot repress activation of the HH signaling pathway and Ptch2 knockout mice do not show significant phenotypes (Lee et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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Patched1 (PTCH1) is one of the key molecules involved in the Hedgehog (HH) signaling pathway and acts as the receptor of HH ligands. Additionally, PTCH1 inhibits the positive signal transductor Smoothened (SMO). Several PTCH1 splice variants are known but the functional differences among them are not clear. Here, we demonstrate the unique biological properties of the PTCH1 isoforms generated by alternative first exon usage. All isoforms examined worked as functional receptors of both Sonic HH and Desert HH. However, the signaling upregulated isoforms PTCH1-1B and -1C inhibited SMO and the pathway transcription factors glioma 1 (GLI1) and GLI2 to a higher extent than PTCH1-1 and -1Ckid. Moreover, in situ hybridizations allowed the detection of the Ptch1 isoforms in specific structures of the developing mouse embryo. Additionally, the differences in the N-terminal tail had a dramatic influence on the steady states of the proteins, with PTCH1-1B and -1C levels being significantly higher than PTCH1-1 and -1Ckid. This implies that the pronounced signaling inhibitory properties of PTCH1-1B and -1C may be mostly due to this high-protein expression rather than to intrinsic functional differences. Thus, our study supports a role of splicing variation and promoter choice for HH signaling regulation.

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Section: Introductionmentioning

confidence: 99%

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

et al. 2007

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“…In contrast to Drosophila, vertebrates possess two additional cell surface HH-binding proteins that are induced by HH signaling: hedgehog interacting protein 1 (HHIP1; HHIP -Mouse Genome Informatics) (Chuang and McMahon, 1999), a membrane-anchored glycoprotein, and patched 2 (PTCH2; Motoyama et al, 1998b), a structural homolog of PTCH1 that arose from a gene duplication event. HHIP1 acts partially redundantly with PTCH1 to antagonize HH signaling in the developing mouse central nervous system (CNS); embryos lacking both HHIP1-and PTCH1-feedback inhibition generate cell fates within the normal HH signaling domain that are more ventral than expected, and HH responses extend into dorsal regions that do not normally exhibit active signaling (Jeong and McMahon, 2005).…”

Section: Introductionmentioning

confidence: 99%

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

et al. 2013

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SUMMARYHedgehog (HH) signaling is essential for vertebrate and invertebrate embryogenesis. In Drosophila, feedback upregulation of the HH receptor Patched (PTC; PTCH in vertebrates), is required to restrict HH signaling during development. By contrast, PTCH1 upregulation is dispensable for early HH-dependent patterning in mice. Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2. Although HHIP1 functions semi-redundantly with PTCH1 to restrict HH signaling in the developing nervous system, a role for PTCH2 remains unresolved. Data presented here define a novel role for PTCH2 as a ciliary localized HH pathway antagonist. While PTCH2 is dispensable for normal ventral neural patterning, combined removal of PTCH2-and PTCH1-feedback antagonism produces a significant expansion of HH-dependent ventral neural progenitors. Strikingly, complete loss of PTCH2-, HHIP1-and PTCH1-feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation. Overall, these data reveal an essential role for liganddependent feedback inhibition of vertebrate HH signaling governed collectively by PTCH1, PTCH2 and HHIP1.

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“…Upon binding to Hh ligands, the inhibition of Smo is released and signaling is transduced, leading to the activation of target genes by the GLi family of transcription factors. [10][11][12][13][14][15] PTCH1 is one of the target genes whose expression is regulated by its alternative promoters and mainly by a single functional GLi-binding site, thus generating a negative feedback loop, which plays an important role in Hh pathway regulation. 8,16 Therefore, expression of PTCH1, Smo and GLi is presumed to be the markers of the Hh pathway activation.…”

Section: Introductionmentioning

confidence: 99%

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

Gao

Chen

et al. 2006

Gene Ther

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Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog

Cited by 197 publications

References 19 publications

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

Antisense Smo under the control of the PTCH1 promoter delivered by an adenoviral vector inhibits the growth of human pancreatic cancer

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