An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

Adolphe, Christelle; Narang, Monica A.; Ellis, Tammy; Wicking, Carol; Kaur, Pritinder; Wainwright, Brandon

doi:10.1242/dev.01367

Cited by 94 publications

(84 citation statements)

References 39 publications

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“…A study of transgenic mice showed that overexpression of Dhh induced skin tumor formation. (32) The present report is the first report suggesting the importance of the upregulation of Dhh, not Shh, in the prognosis of cancer patients. However, our multivariate analysis showed that Dhh expression was not an independent prognostic factor, and the number of patients in this study was small.…”

Section: Discussionmentioning

confidence: 53%

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

et al. 2006

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The hedgehog (Hh) signal pathway has recently been shown to be activated in human malignancies. However, little is known about its role in the development or patient prognosis of epithelial ovarian carcinoma. In the present study, we examined in vivo and in vitro E pithelial ovarian carcinoma, which comprises the majority of malignant ovarian tumors, is the leading cause of death from gynecologic malignancy in women.(1) The survival of ovarian carcinoma patients has not improved significantly for years, indicating that further understanding of the biology of ovarian carcinoma cells is critical for the development of new treatments against this neoplasm.(2) Several studies have reported that the poor prognosis of ovarian carcinoma is related not only to the unique metastasis but also to the high proliferative activity of carcinoma cells.(3-5) However, the molecular mechanisms of the proliferation of ovarian carcinoma cells are not fully understood. Recent studies suggest that the hedgehog (Hh) signal pathway contributes to cell proliferation and differentiation in several human neoplasms, such as pancreas, prostate and skin carcinomas.

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Section: Discussionmentioning

confidence: 53%

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

et al. 2006

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“…Dhh is a functional homologue of Shh activity during epidermal stem cell homeostasis and skin tumor formation; activation of an ectopic Dhh pathway regulates epidermal basal cell proliferation. 31 Dhh expression was upregulated in PAX3c and PAX3e transfectants at both mRNA and protein levels, but the protein was downregulated in PAX3g transfectants. Further studies are required to ascertain whether PAX3 isoforms directly regulate Dhh.…”

Section: Discussionmentioning

confidence: 89%

Investigation of downstream target genes of PAX3c, PAX3e and PAX3g isoforms in melanocytes by microarray analysis

Wang

Kumar

Mitsios

et al. 2006

Intl Journal of Cancer

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PAX3 encodes a transcription factor, which with Zic1 is necessary for induction of the neural crest during early embryonic development. There are 7 human PAX3 isoforms (a–h). PAX3e is the full length isoform comprising 10 exons. PAX3c comprises 8 exons plus 5 codons of intron 8, while PAX3g has a truncated transactivation domain. Previous studies by us indicated that these isoforms have different activities in melanocytes in vitro. In this study, a mouse gene oligo array (∼7.5 k oligos), from the Human Genome Mapping Project (HGMP) Resource Centre, was used to screen for alterations in downstream gene expression in PAX3c, PAX3e and PAX3g melanocyte transfectants, compared with empty vector controls. The data analyses identified 109 genes up or downregulated, at least 2‐fold, and involved in cell differentiation, proliferation, migration, adhesion, apoptosis and angiogenesis. Semi‐quantitative RT‐PCR and Western blotting confirmed the changes identified by microarrays for several putative targets of PAX3, including Met, MyoD and Muc18, and previously undescribed targets, including Dhh, Fgf17, Kitl and Rac1. Thus, our data reveal that PAX3 isoforms regulate distinct but overlapping sets of genes in melanocytes in vitro. © 2006 Wiley‐Liss, Inc.

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“…Fourteen-micrometer-thick RNase-free sagittal sections of the central nervous system, medial to the vermis, were labeled using 500 ng of the Atoh1 riboprobe as previously described (Adolphe et al 2004). The Atoh1 riboprobe was generated using the primers SP6 forward (59-GCG ATT TAG GTG ACA CTA TAG GAC CAC CAT CAC CTT CGC-39) and T7 reverse (59-GCG TGT ATT CTG GGT CCG CCC TAT AGT GAG TCG TAT TAA CAT CG-39) to create a 877-nt product.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

Constantin

Wainwright

2016

Genetics

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The Dicer1, Dcr-1 homolog (Drosophila) gene encodes a type III ribonuclease required for the canonical maturation and functioning of microRNAs (miRNAs). Subsets of miRNAs are known to regulate normal cerebellar granule cell development, in addition to the growth and progression of medulloblastoma, a neoplasm that often originates from granule cell precursors. Multiple independent studies have also demonstrated that deregulation of Sonic Hedgehog (Shh)-Patched (Ptch) signaling, through miRNAs, is causative of granule cell pathologies. In the present study, we investigated the genetic interplay between miRNA biogenesis and Shh-Ptch signaling in granule cells of the cerebellum by way of the Cre/lox recombination system in genetically engineered models of Mus musculus (mouse). We demonstrate that, although the miRNA biogenesis and Shh-Ptch-signaling pathways, respectively, regulate the opposing growth processes of cerebellar hypoplasia and hyperplasia leading to medulloblastoma, their concurrent deregulation was nonadditive and did not bring the growth phenotypes toward an expected equilibrium. Instead, mice developed either hypoplasia or medulloblastoma, but of a greater severity. Furthermore, some genotypes were bistable, whereby subsets of mice developed hypoplasia or medulloblastoma. This implies that miRNAs and Shh-Ptch signaling regulate an important developmental transition in granule cells of the cerebellum. We also conclusively show that the Dicer1 gene encodes a haploinsufficient tumor suppressor gene for Ptch1-induced medulloblastoma, with the monoallielic loss of Dicer1 more severe than biallelic loss. These findings exemplify how genetic interplay between pathways may produce nonadditive effects with a substantial and unpredictable impact on biology. Furthermore, these findings suggest that the functional dosage of Dicer1 may nonadditively influence a wide range of Shh-Ptch-dependent pathologies.

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An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

Abstract: SummaryAn in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis

Cited by 94 publications

References 39 publications

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

Investigation of downstream target genes of PAX3c, PAX3e and PAX3g isoforms in melanocytes by microarray analysis

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

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