Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of P13K/Akt signaling

Debottam Sinha, Murugan Kalimutho, Josephine Bowles, Ai-Leen Chan, D. Jo Merriner, Amanda L Bain, Jacinta L. Simmons, Raimundo Freire, J. Alejandro Lopez, Robin M. Hobbs, Moira K. O'Bryan, Kum Kum Khanna

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Abstract

Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein (CEP)-55 is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 protein (TEX14), has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic mice (Cep55Tg/Tg) aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55Tg/Tg male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) –positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret (Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 (Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 (Egr4) and spermatogenesis and oogenesis specific basic helix–loop–helix-1 (Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.—Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O’Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.
Original languageEnglish
Pages (from-to)4984-4999
Number of pages16
JournalFASEB Journal
Volume32
Issue number9
DOIs
Publication statusPublished - Sep 2018

Keywords

  • spermatogenesis
  • mouse model
  • azoospermia
  • male infertility

Cite this

Sinha, Debottam ; Kalimutho, Murugan ; Bowles, Josephine ; Chan, Ai-Leen ; Merriner, D. Jo ; Bain, Amanda L ; Simmons, Jacinta L. ; Freire, Raimundo ; Lopez, J. Alejandro ; Hobbs, Robin M. ; O'Bryan, Moira K. ; Khanna, Kum Kum. / Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of P13K/Akt signaling. In: FASEB Journal. 2018 ; Vol. 32, No. 9. pp. 4984-4999.
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abstract = "Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein (CEP)-55 is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 protein (TEX14), has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic mice (Cep55Tg/Tg) aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55Tg/Tg male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) –positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret (Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 (Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 (Egr4) and spermatogenesis and oogenesis specific basic helix–loop–helix-1 (Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.—Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O’Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.",
keywords = "spermatogenesis, mouse model, azoospermia, male infertility",
author = "Debottam Sinha and Murugan Kalimutho and Josephine Bowles and Ai-Leen Chan and Merriner, {D. Jo} and Bain, {Amanda L} and Simmons, {Jacinta L.} and Raimundo Freire and Lopez, {J. Alejandro} and Hobbs, {Robin M.} and O'Bryan, {Moira K.} and Khanna, {Kum Kum}",
year = "2018",
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doi = "10.1096/fj.201701096RR",
language = "English",
volume = "32",
pages = "4984--4999",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "Federation of American Societies for Experimental Biology",
number = "9",

}

Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of P13K/Akt signaling. / Sinha, Debottam; Kalimutho, Murugan; Bowles, Josephine; Chan, Ai-Leen; Merriner, D. Jo; Bain, Amanda L; Simmons, Jacinta L.; Freire, Raimundo; Lopez, J. Alejandro; Hobbs, Robin M.; O'Bryan, Moira K.; Khanna, Kum Kum.

In: FASEB Journal, Vol. 32, No. 9, 09.2018, p. 4984-4999.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of P13K/Akt signaling

AU - Sinha, Debottam

AU - Kalimutho, Murugan

AU - Bowles, Josephine

AU - Chan, Ai-Leen

AU - Merriner, D. Jo

AU - Bain, Amanda L

AU - Simmons, Jacinta L.

AU - Freire, Raimundo

AU - Lopez, J. Alejandro

AU - Hobbs, Robin M.

AU - O'Bryan, Moira K.

AU - Khanna, Kum Kum

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N2 - Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein (CEP)-55 is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 protein (TEX14), has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic mice (Cep55Tg/Tg) aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55Tg/Tg male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) –positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret (Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 (Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 (Egr4) and spermatogenesis and oogenesis specific basic helix–loop–helix-1 (Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.—Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O’Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.

AB - Spermatogenesis is a dynamic process involving self-renewal and differentiation of spermatogonial stem cells, meiosis, and ultimately, the differentiation of haploid spermatids into sperm. Centrosomal protein (CEP)-55 is necessary for somatic cell abscission during cytokinesis. It facilitates equal segregation of cytoplasmic contents between daughter cells by recruiting endosomal sorting complex required for transport machinery (ESCRT) at the midbody. In germ cells, CEP55, in partnership with testes expressed-14 protein (TEX14), has also been shown to be an integral component of intercellular bridge before meiosis. Various in vitro studies have demonstrated a role for CEP55 in multiple cancers and other diseases. However, its oncogenic potential in vivo remains elusive. To investigate, we generated ubiquitously overexpressing Cep55 transgenic mice (Cep55Tg/Tg) aiming to characterize its oncogenic role in cancer. Unexpectedly, we found that Cep55Tg/Tg male mice were sterile and had severe and progressive defects in spermatogenesis related to spermatogenic arrest and lack of spermatids in the testes. In this study, we characterized this male-specific phenotype and showed that excessively high levels of Cep55 results in hyperactivation of PI3K/protein kinase B (Akt) signaling in testis. In line with this finding, we observed increased phosphorylation of forkhead box protein O1 (FoxO1), and suppression of its nuclear retention, along with the relative enrichment of promyelocytic leukemia zinc finger (PLZF) –positive cells. Independently, we observed that Cep55 amplification favored upregulation of ret (Ret) proto-oncogene and glial-derived neurotrophic factor family receptor α-1 (Gfra1). Consistent with these data, we observed selective down-regulation of genes associated with germ cell differentiation in Cep55-overexpressing testes at postnatal day 10, including early growth response-4 (Egr4) and spermatogenesis and oogenesis specific basic helix–loop–helix-1 (Sohlh1). Thus, Cep55 amplification leads to a shift toward the initial maintenance of undifferentiated spermatogonia and ultimately results in progressive germ cell loss. Collectively, our findings demonstrate that Cep55 overexpression causes change in germ cell proportions and manifests as a Sertoli cell only tubule phenotype, similar to that seen in many azoospermic men.—Sinha, D., Kalimutho, M., Bowles, J., Chan, A.-L., Merriner, D. J., Bain, A. L., Simmons, J. L., Freire, R., Lopez, J. A., Hobbs, R. M., O’Bryan, M. K., Khanna, K. K. Cep55 overexpression causes male-specific sterility in mice by suppressing Foxo1 nuclear retention through sustained activation of PI3K/Akt signaling.

KW - spermatogenesis

KW - mouse model

KW - azoospermia

KW - male infertility

U2 - 10.1096/fj.201701096RR

DO - 10.1096/fj.201701096RR

M3 - Article

VL - 32

SP - 4984

EP - 4999

JO - FASEB Journal

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