Impaired fertility in mice deficient for the testicular germ-cell protease PC4

Mbikay, Majambu; Tadros, Haidy; Ishida, Norito; Lerner, Charles P.; Lamirande, Eve de; A, Chen; El‐Alfy, Mohamed; Clermont, Y.; Seidah, Nabil G.; Chrétien, Michel; Gagnon, Claude; Simpson, Elizabeth M.

doi:10.1073/pnas.94.13.6842

Cited by 152 publications

(106 citation statements)

References 32 publications

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“…However, a good candidate is the prohormone convertase PC4 because it is abundantly and specifically expressed in the spermatocytes and round spermatids of rodents (38). Moreover, PC4 homozygous mutant males show reduced fertility in the absence of any evidence of spermatogenic abnormality (36), similar to what we observed in Nl1-deficient mice. Interestingly, the reduced fertility of Pc4 Ϫ/Ϫ males is due to a combination of both reduced efficiency in egg fertilization and abnormal embryo development after fertilization.…”

Section: Discussionsupporting

confidence: 76%

Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1

Carpentier

Guillemette

Bailey

et al. 2004

Molecular and Cellular Biology

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Members of the M13 family of zinc metalloendopeptidases have been shown to play critical roles in the metabolism of various neuropeptides and peptide hormones, and they have been identified as important therapeutic targets. Recently, a mouse NL1 protein, a novel member of the family, was identified and shown to be expressed mainly in the testis as a secreted protein. To define its physiological role(s), we used a gene targeting strategy to disrupt the endogenous murine Nl1 gene by homologous recombination and generate Nl1 mutant mice. The Nl1 ؊/؊ mice were viable and developed normally, suggesting that zygotic expression of Nl1 is not required for development. However, Nl1؊/؊ males produced smaller litters than their wild-type siblings, indicating specific male fertility problems. Reduced fertility may be explained by two impaired processes, decreased egg fertilization and perturbed early development of fertilized eggs. These two phenotypes did not result from gross anatomical modifications of the testis or from impaired spermatogenesis. Basic sperm parameters were also normal. Thus, our findings suggest that one of the roles of NL1 in mice is related to sperm function and that NL1 modulates the processes of fertilization and early embryonic development in vivo.A wide variety of biologically active peptide hormones, neuropeptides, and regulatory peptides are proteolytically activated or inactivated by zinc metalloproteases (58, 59). The M13 family of zinc metalloproteases attracts much interest because its members are involved in the metabolism of several regulatory peptides of the mammalian nervous, cardiovascular, inflammatory, and immune systems as well as in the mineralization process (8,56,57,59). For these reasons, several members of this family of peptidases have been selected as targets for therapeutic intervention by inhibitors or pharmacological agents.NL1 (also called SEP or NEP2) is the newest member of the M13 family of zinc metallopeptidases (19,25,42), which also includes neprilysin (neutral endopeptidase 24.11; also called NEP and CALLA) (reviewed in reference 11), the endothelinconverting enzymes 1 and 2 (ECE-1 and ECE-2) (reviewed in reference 55), PHEX (formerly PEX; a phosphate regulating gene with homologies to endopeptidases on the X chromosome) (reviewed in reference 54), the Kell blood group protein (reviewed in reference 35), and ECEL1/DINE (endothelinconverting enzyme-like 1/damage-induced neuronal endopeptidase) (29, 60, 61). Nl1 cDNA was simultaneously cloned by reverse transcription-PCR technology with degenerate oligonucleotide primers based on conserved sequence similarity between members of the family and mRNA isolated from mouse and rat testis or from Ece-1 Ϫ/Ϫ embryos (19,25,42). Finally, a clone coding for a putative human homologue has been obtained from a central nervous system cDNA library (4).As observed for other members of the M13 family of peptidases, the Nl1 cDNA encodes a type II transmembrane glycoprotein encompassing a short N-terminal cytoplasmic tail, a single tran...

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Section: Discussionsupporting

confidence: 76%

Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1

Carpentier

Guillemette

Bailey

et al. 2004

Molecular and Cellular Biology

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“…Although we did not specifically assay PC2 or PC4 for their ability to cleave BMP-4, these enzymes are not appropriate candidate convertases since they are confined to neuroendocrine tissues (Zheng et al, 1994(Zheng et al, , 1997reviewed in Steiner et al, 1992) or to adult testicular germ cells (Nakayama et al, 1992;Mbikay et al, 1997), respectively, while BMP-4 is widely expressed. PACE-4 has been suggested to be an endogenous BMP-convertase, based on the observation that it is co-expressed with BMPs in a number of embryonic tissues (Constam et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development

et al. 1998

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“…The restricted tissue expression, acidic pH optima, and regulated pathway localization of the neuroendocrine-specific PC1/3 (hereafter termed PC3) and PC2 reflect their specialized function in the processing of prohormone substrates (Seidah et al, 1994;Nakayama, 1997;Steiner, 1998). Similarly, the unique expression of PC4 in the testes, together with impaired fertility in PC4-knockout mice (Mbikay et al, 1997), indicates a highly specialized function for this convertase. Several other PCs, however, have broader, overlapping expression patterns in a large number of tissues and cell types (Seidah et al, 1994;Steiner, 1998).…”

Section: Introductionmentioning

confidence: 99%

The PC6B Cytoplasmic Domain Contains Two Acidic Clusters That Direct Sorting to Distincttrans-Golgi Network/Endosomal Compartments

Xiang

Molloy

Thomas

et al. 2000

MBoC

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The mammalian proprotein convertases (PCs) are a family of secretory pathway enzymes that catalyze the endoproteolytic maturation of peptide hormones and many bioactive proteins. Two PCs, furin and PC6B, are broadly expressed and share very similar cleavage site specificities, suggesting that they may be functionally redundant. However, germline knockout studies show that they are not. Here we report the distinct subcellular localization of PC6B and identify the sorting information within its cytoplasmic domain (cd). We show that in neuroendocrine cells, PC6B is localized to a paranuclear, brefeldin A-dispersible, BaCl 2 -responsive post-Golgi network (TGN) compartment distinct from furin and TGN38. The 88-amino acid PC6B-cd contains sorting information sufficient to direct reporter proteins to the same compartment as full-length PC6B. Mutational analysis indicates that endocytosis is predominantly directed by a canonical tyrosinebased motif (Tyr 1802 GluLysLeu). Truncation and sufficiency studies reveal that two clusters of acidic amino acids (ACs) within the PC6B-cd contain differential sorting information. The membrane-proximal AC (AC1) directs TGN localization and interacts with the TGN sorting protein PACS-1. The membrane-distal AC (AC2) promotes a localization characteristic of the full-length PC6B-cd. Our results demonstrate that AC motifs can target proteins to distinct TGN/endosomal compartments and indicate that the AC-mediated localization of PC6B and furin contribute to their distinct roles in vivo.

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Impaired fertility in mice deficient for the testicular germ-cell protease PC4

Cited by 152 publications

References 32 publications

Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1

Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1

BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development

The PC6B Cytoplasmic Domain Contains Two Acidic Clusters That Direct Sorting to Distincttrans-Golgi Network/Endosomal Compartments

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