Adult testicular dysgenesis of
            <i>Inhba</i>
            conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells

Sun, Zhanfang; Li, Zhen; Zhang, Yuanqiang

doi:10.1073/pnas.1008771107

Cited by 2 publications

(3 citation statements)

References 4 publications

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“…Platelet-derived growth factor ( PDGF ), a key regulator of connective tissue cells during embryogenesis and pathogenesis, was one of the locally produced growth factors that mediate testicular cell-cell interactions ( Mariani et al, 2002 ). It was reported that adult testicular dysgenesis was triggered in Inhba conditional knockout mice, which was explained by the fact that cross-talk between Leydig cells and germ cells was disrupted ( Sun et al, 2010 ). Therefore, we speculated that INHBA (inhibin subunit beta A) was critical for physical interactions between germ and somatic cells from immature testicular development in the ovine newborn-infant phase.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes Related to Postnatal Testicular Development Based on Transcriptomic Data of Testis in Hu Sheep

Sun

Pei

et al. 2022

Front. Genet.

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The selection of testis size can improve the reproductive capacity of livestock used for artificial insemination and has been considered as an important strategy for accelerating the breeding process. Although much work has been done to investigate the mechanisms of testis development in various species, there is little information available in regard to the differences in transcriptomic profiling of sheep testes at different developmental stages. In this work, we aimed to identify differentially expressed genes (DEGs) by RNA-Seq in sheep during different growth stages, including 0 month old (infant, M0), 3 months old (puberty, M3), 6 months old (sexual maturity, M6) and 12 months old (body maturity, M12). A total of 4,606 (2,381 up and 2,225 down), 7,500 (4,368 up and 3,132 down), 15 (8 up and seven down) DEGs were identified in M3_vs_M0, M6_vs_M3, and M12_vs_M6 comparison, respectively. Of which, a number of genes were continuously up-regulated and down-regulated with testicular development, including ODF3, ZPBP1, PKDREJ, MYBL1, PDGFA, IGF1, LH, INSL3, VIM, AMH, INHBA, COL1A1, COL1A2, and INHA. GO analysis illustrated that DEGs were mainly involved in testis development and spermatogenesis. KEGG analysis identified several important pathways and verified several reproduction-associated DEGs such as COL1A1, COL1A2, PDGFA, and IGF1. In addition, two gene modules highly associated with testis development and core genes with testis size were identified using weighted gene co-expression network analysis (WGCNA), including hub genes positively associated with testis size such as RANBP9, DNAH17, SPATA4, CIB4 and SPEM1, and those negatively associated with testis size such as CD81, CSK, PDGFA, VIM, and INHBA. This study comprehensively identified key genes related to sheep testicular development, which may provide potential insights for understanding male fertility and better guide in animal breeding.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes Related to Postnatal Testicular Development Based on Transcriptomic Data of Testis in Hu Sheep

Sun

Pei

et al. 2022

Front. Genet.

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“…Alternatively, it is possible that compensatory factors make up for the loss of activin A production by Leydig cells in juvenile Inhba cKO mice. We sincerely appreciate the concerns raised by Sun et al (2) and are pleased that our research prompted this stirring scientific discussion. …”

mentioning

confidence: 99%

“…With regard to our publication in PNAS (1), the letter by Sun et al (2) raises an excellent point in stressing the possible effects of adult Leydig cell-derived activin A on developing germ cells. In their letter, Sun et al (2) provide a judicious reminder of an issue that we discussed many times during collection of this data-namely, what role does loss of adult Leydig cell-derived activin A play in the testicular phenotype that we observed in adult Inhba conditional knockout (cKO) mice? As presented in our PNAS article (1), conditional removal of Inhba within Amhr2-positive Leydig cells led to obvious fetal defects, including reduced coiling of testis cords and enlargement of testis cord diameter.…”

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confidence: 99%

Reply to Sun et al.: Roles of adult Leydig cell-derived activin A remain to be determined

Archambeault¹,

Yao²

2010

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

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The complicated and sometimes confusing relationship between activin A and germ cell development has been studied for many decades both in vitro and in vivo. With regard to our publication in PNAS (1), the letter by Sun et al. (2) raises an excellent point in stressing the possible effects of adult Leydig cell-derived activin A on developing germ cells. In their letter, Sun et al. (2) provide a judicious reminder of an issue that we discussed many times during collection of this data-namely, what role does loss of adult Leydig cell-derived activin A play in the testicular phenotype that we observed in adult Inhba conditional knockout (cKO) mice? As presented in our PNAS article (1), conditional removal of Inhba within Amhr2-positive Leydig cells led to obvious fetal defects, including reduced coiling of testis cords and enlargement of testis cord diameter. By the time that the Inhba cKO mice were young adults, their testes exhibited enlarged seminiferous tubule diameter and various spermatogenic abnormalities. As Sun et al. (2) pointed out, the Amhr2-cre used to excise Inhba in fetal Leydig cells is also expressed in adult Leydig cells (3). Thus, the Inhba cKO mouse model that we developed is not able to clarify whether the adult testicular dysgenesis is caused solely by fetal defects or whether it additionally reflects the disruption of postnatal activin A production by adult Leydig cells.In contrast to the Inhba cKO mouse model, the Smad4 cKO model described in this article is only lacking Smad4 expression within Sertoli cells. Leydig cell expression of activin A, as well as the ability of germ cells to respond to activin A, should be intact. Based on our fetal analysis, the testis cord dysgenesis observed in Inhba cKO and Smad4 cKO models was grossly similar, although Sertoli cell proliferation was significantly reduced in the Smad4 cKO model compared with Inhba cKO mice. Given the general similarities in fetal phenotype between our two models, we argue that, if Leydig cell-derived activin A was critical for any aspect of postnatal testis development, we should logically observe more severe testicular dysgenesis in adult Inhba cKO males compared with Smad4 cKO mice. For example, if postnatal activin A from adult Leydig cells was absolutely essential for germ cell development, we would anticipate dramatic reductions in sperm output and/or extremely aberrant appearance of the seminiferous epithelium in Inhba cKO males compared with Smad4 cKO males. Instead, we observed grossly similar dysfunctions between adult Inhba cKO and Smad4 cKO testes, namely reduced testis size, decreased daily sperm production, and remarkably similar seminiferous tubule histology.Although our results do not completely rule out a role for adult Leydig cell-derived activin A in postnatal testis development, they suggest that perhaps its role is not as critical as has been postulated. Alternatively, it is possible that compensatory factors make up for the loss of activin A production by Leydig cells in juvenile Inhba cKO mice. We sincere...

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Adult testicular dysgenesis of Inhba conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells

Cited by 2 publications

References 4 publications

Identification of Key Genes Related to Postnatal Testicular Development Based on Transcriptomic Data of Testis in Hu Sheep

Identification of Key Genes Related to Postnatal Testicular Development Based on Transcriptomic Data of Testis in Hu Sheep

Reply to Sun et al.: Roles of adult Leydig cell-derived activin A remain to be determined

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