GLI1 Localization in the Germinal Epithelial Cells Alternates Between Cytoplasm and Nucleus: Upregulation in Transgenic Mice Blocks Spermatogenesis in Pachytene1

Kroft, Tim L.; Patterson, J. T.; Yoon, Joon Won; Doglio, Lynn; Walterhouse, David; Iannaccone, Phillip; Goldberg, Erwin

doi:10.1095/biolreprod65.6.1663

Cited by 48 publications

(40 citation statements)

References 27 publications

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“…We were unable to obtain a signal with commercial preparations of antibodies to Gli1 or Gli3, either on Western blots or on immunohistochemistry (data not shown) to confirm these data. In the present study, it is in the elongating spermatids that the signal for SuFu protein appears most intense, and it is in these cells that Gli1 protein had been reported to shift to the cytoplasm (Kroft et al, 2001). This pattern indicates SuFu may be acting to switch off the Hh pathway in the round and elongating spermatids of the adult mouse testis.…”

Section: Discussionsupporting

confidence: 48%

“…SuFu has also been shown to suppress Gli-mediated transcription by recruiting the mSin3-histone deacetylase corepressor complex to Gli promoters (Cheng and Bishop, 2002). According to published reports, Gli1 protein is present in the nucleus of pachytene spermatocytes and round spermatids (Kroft et al, 2001). We were unable to obtain a signal with commercial preparations of antibodies to Gli1 or Gli3, either on Western blots or on immunohistochemistry (data not shown) to confirm these data.…”

Section: Discussionmentioning

confidence: 99%

“…Gli1 protein has been localized to the nuclei of germ cells, its detection beginning in pachytene spermatocytes and persisting through to round spermatids in the adult mouse testis. Its localization was reported to shift from the nucleus to the cytoplasm in elongating spermatids (Kroft et al, 2001), indicating that Gli1-mediated transcriptional effects are switched off at the elongating spermatid stage of germ cell maturation. When human Gli1 was overexpressed in germ cells of mice under the control of the zinc-inducible mouse metallothionein-1 (MT-1) promoter, spermatogenesis was blocked at the pachytene spermatocyte stage, providing evidence that dysregulated activation of Gli1 target genes could disrupt normal spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Expression of hedgehog signalling components in adult mouse testis

Szczepny

Hime

Loveland

2006

Developmental Dynamics

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Hedgehog (Hh) signalling is known to regulate many aspects of normal development as well as being upregulated in various cancers. Signalling is mediated by the Gli family of zinc finger transcription factors. Based on observations that deletion of one of the three Hh genes, Dhh, leads to male infertility, we hypothesized that regulated expression of Hh signalling components would be a feature of adult spermatogenesis. We used in situ hybridization to characterise Gli gene expression in juvenile and adult mouse testes. In the first wave of spermatogenesis, mRNAs encoding all three Glis are detected in spermatogonia and Sertoli cells. In adult mouse testes, these transcripts are observed in spermatogonia and spermatocytes, with reduced signal intensity in round spermatids. The mRNAs encoding key effectors of Hh signalling, Ptc2, Smo, and Fu, are also most apparent in spermatogonia, spermatocytes, and to a lower extent in round spermatids. In contrast, mRNA encoding SuFu, a negative regulator of Hh signalling, was most predominant in round spermatids and the protein is evident in round and elongating spermatids, suggesting that SuFu protein may switch off Hh signalling in haploid germ cells. Overall, the coordinated expression pattern of these genes in adult mouse testis indicates a role for Hh signalling in spermatogenesis.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression of hedgehog signalling components in adult mouse testis

Szczepny

Hime

Loveland

2006

Developmental Dynamics

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“…The nuclear accumulation of GLI1 in undifferentiated sebocytes in vivo is an indication of active Hh signaling (53)(54)(55)(56). The negative effect of cyclopamine on proliferation of undifferentiated sebocytes in vitro is direct evidence that IHH stimulates proliferation of sebaceous progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

Niemann

Undén

Lyle

et al. 2003

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

174

140

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In mammalian epidermis, the level of ␤-catenin signaling regulates lineage selection by stem cell progeny. High levels of ␤-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of ␤-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks ␤-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of ␤-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor, Patched (PTCH͞Ptch). In ⌬NLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of ⌬NLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between ␤-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.

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“…The Hedgehog pathway is also critical for foetal gonad development. Hedgehog signalling in the mammalian testis is involved in communicating between Sertoli and Leydig cells, germ cells (Kroft et al 2001) and peritubular cells (Clark et al 2000). The Hedgehog family member desert Hedgehog (Dhh) was found to be expressed in Sertoli cell precursors shortly after the activation of Sry and persists in these cells into adulthood (Bitgood et al 1996, Szczepny et al 2006.…”

Section: Discussionmentioning

confidence: 99%

Expression of Wsb2 in the developing and adult mouse testis

Sarraj

McClive²,

Szczepny

et al. 2007

Reproduction

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We present a detailed study of the expression pattern of WD repeat and SOCS box-containing 2 (Wsb2) in mouse embryonic and adult gonads. Wsb2 was previously identified in a differential screen aimed at identifying the genes involved in male-and femalespecific gonadal development. Wsb2 expression was analysed during mouse gonadogenesis by real-time PCR, whole-mount and section in situ hybridisation and immunofluorescence. Wsb2 mRNA expression was initially detected in gonads of both sexes from 11.5 days post coitum (dpc) until 12.0 dpc. By 12.5 dpc and thereafter, Wsb2 expression rapidly decreased in the female, while persisting in the male gonads. In foetal, newborn and juvenile testes, Wsb2 mRNA and protein were readily detected in the seminiferous cords within both Sertoli and germ cells. Wsb2 mRNA was present in spermatogonia, spermatocytes and in Sertoli cells of the adult mouse testis. The differential expression of Wsb2 in male versus female embryonic gonads suggests some male-specific role in gonad development, and its expression in the first wave of spermatogenesis indicates a role in germ cells. Real-time analysis of adult mouse testis tubules cultured in the presence of the Hedgehog signalling inhibitor, cyclopamine, showed a downregulation of Wsb2 mRNA after treatment which suggests that Wsb2 may be a target of Hedgehog signalling.

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GLI1 Localization in the Germinal Epithelial Cells Alternates Between Cytoplasm and Nucleus: Upregulation in Transgenic Mice Blocks Spermatogenesis in Pachytene1

Cited by 48 publications

References 27 publications

Expression of hedgehog signalling components in adult mouse testis

Expression of hedgehog signalling components in adult mouse testis

Indian hedgehog and β-catenin signaling: Role in the sebaceous lineage of normal and neoplastic mammalian epidermis

Expression of Wsb2 in the developing and adult mouse testis

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