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Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Formation and Function in Assisted Fertilization.

Yamauchi Y, Riel JM, Ruthig V, Ward MA - PLoS Genet. (2015)

Bottom Line: Spermatogenesis is a key developmental process allowing for a formation of a mature male gamete.During its final phase, spermiogenesis, haploid round spermatids undergo cellular differentiation into spermatozoa, which involves extensive restructuring of cell morphology, DNA, and epigenome.Therefore, only three Y chromosome genes, Sry, Eif2s3y and Zfy2, constitute the minimum Y chromosome complement compatible with successful intracytoplasmic sperm injection in the mouse.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.

ABSTRACT
Spermatogenesis is a key developmental process allowing for a formation of a mature male gamete. During its final phase, spermiogenesis, haploid round spermatids undergo cellular differentiation into spermatozoa, which involves extensive restructuring of cell morphology, DNA, and epigenome. Using mouse models with abrogated Y chromosome gene complements and Y-derived transgene we identified Y chromosome encoded Zfy2 as the gene responsible for sperm formation and function. In the presence of a Zfy2 transgene, mice lacking the Y chromosome and transgenic for two other Y-derived genes, Sry driving sex determination and Eif2s3y initiating spermatogenesis, are capable of producing sperm which when injected into the oocytes yield live offspring. Therefore, only three Y chromosome genes, Sry, Eif2s3y and Zfy2, constitute the minimum Y chromosome complement compatible with successful intracytoplasmic sperm injection in the mouse.

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Mouse X and Y chromosomes, variant sex chromosomes, and mouse genotypes relevant to this study.(A) The mouse Y chromosome contains ~90 Mb of male specific DNA and ~0.7 Mb constituting the pseudoautosomal region (PAR) situated at the end of the long arm. The PAR is the region of homology with the X that mediates pairing and recombination between the X and Y in normal males. The remaining non-pairing male specific part of Y (NPY) contains several genes and gene families. On the short arm (NPYp), there are single-copy genes: Prssly, Teyorf1, Uba1y, Smcy/Kdm5d, Eif2s3y, Uty, Dby/Ddx3y, Usp9y, Sry, duplicated gene Zfy (Zfy1 and 2), duplicated gene H2al2y, and a multi-copy gene Rbmy. The non-pairing region of the long arm (NPYq), representing ~90% of all NPY, contains mostly repetitive sequences, and encodes multiple copies of 5 distinct genes that are expressed in spermatids: Ssty1 and Ssty2, Sly, Srsy, Rbm31y [6]. Y*X is an X chromosome derivative encoding PAR, X centromere and near centromeric region. Sxra is a sex reversal variant Tp(Y)1CtSxr-a encoding almost intact NPYp complement but with Rbmy gene family reduced. Sxrbis a Sxra derivative with a 1.3 Mb deletion that has removed the majority of the NPYp gene complement and created a Zfy2/1 fusion gene. (B) The mice used in this study and their Y chromosome contribution. The X chromosome located Eif2s3y and autosomally located Sry transgenes, are shown in light blue frames. The Zfy2 transgene, shown in brown frame, is located on the X chromosome in the Hrpt locus in close proximity to the Eif2s3y transgene. The genotype designations without the Zfy2 transgene are shown above the diagrammatic representation of sex chromosomes and with the Zfy2 transgene below them (brown font). Sxra and Sxrb gene content is shown in A. n/a = mice with transgenic Zfy2 addition were either not produced or not examined in this study.
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pgen.1005476.g001: Mouse X and Y chromosomes, variant sex chromosomes, and mouse genotypes relevant to this study.(A) The mouse Y chromosome contains ~90 Mb of male specific DNA and ~0.7 Mb constituting the pseudoautosomal region (PAR) situated at the end of the long arm. The PAR is the region of homology with the X that mediates pairing and recombination between the X and Y in normal males. The remaining non-pairing male specific part of Y (NPY) contains several genes and gene families. On the short arm (NPYp), there are single-copy genes: Prssly, Teyorf1, Uba1y, Smcy/Kdm5d, Eif2s3y, Uty, Dby/Ddx3y, Usp9y, Sry, duplicated gene Zfy (Zfy1 and 2), duplicated gene H2al2y, and a multi-copy gene Rbmy. The non-pairing region of the long arm (NPYq), representing ~90% of all NPY, contains mostly repetitive sequences, and encodes multiple copies of 5 distinct genes that are expressed in spermatids: Ssty1 and Ssty2, Sly, Srsy, Rbm31y [6]. Y*X is an X chromosome derivative encoding PAR, X centromere and near centromeric region. Sxra is a sex reversal variant Tp(Y)1CtSxr-a encoding almost intact NPYp complement but with Rbmy gene family reduced. Sxrbis a Sxra derivative with a 1.3 Mb deletion that has removed the majority of the NPYp gene complement and created a Zfy2/1 fusion gene. (B) The mice used in this study and their Y chromosome contribution. The X chromosome located Eif2s3y and autosomally located Sry transgenes, are shown in light blue frames. The Zfy2 transgene, shown in brown frame, is located on the X chromosome in the Hrpt locus in close proximity to the Eif2s3y transgene. The genotype designations without the Zfy2 transgene are shown above the diagrammatic representation of sex chromosomes and with the Zfy2 transgene below them (brown font). Sxra and Sxrb gene content is shown in A. n/a = mice with transgenic Zfy2 addition were either not produced or not examined in this study.

Mentions: We recently investigated spermatogenesis progression and germ cell function in male mice with significantly abrogated Y chromosome complements [5]. We have shown that males with the Y chromosome contribution provided by two transgenes, the testis determinant Sry and the spermatogonial proliferation factor Eif2s3y (Fig 1B, XEOSry and XEY*XSry) have meiotic and postmeiotic arrest, the rare spermatids present in the testes do not elongate, and sperm are not formed. When round spermatids from these males were injected into the oocytes, live mouse progeny were obtained. The success of round spermatid injection (ROSI) was low, with less than 10% of transplanted embryos developing to live offspring. Interestingly, when the Sry transgene was replaced with the Y chromosome derived sex reversal factor Sxrb, encoding for Sry, H2al2y, Prssly, Teyorf1, Rbmy gene cluster, and Zfy2/1 fusion gene (Fig 1A, Sxrb) the resulting males (Fig 1B, XESxrbO and XESxrbY*X) had more advanced spermatid development with clear elongation of these cells, occasional appearance of sperm, and increased ROSI efficiency.


Mouse Y-Encoded Transcription Factor Zfy2 Is Essential for Sperm Formation and Function in Assisted Fertilization.

Yamauchi Y, Riel JM, Ruthig V, Ward MA - PLoS Genet. (2015)

Mouse X and Y chromosomes, variant sex chromosomes, and mouse genotypes relevant to this study.(A) The mouse Y chromosome contains ~90 Mb of male specific DNA and ~0.7 Mb constituting the pseudoautosomal region (PAR) situated at the end of the long arm. The PAR is the region of homology with the X that mediates pairing and recombination between the X and Y in normal males. The remaining non-pairing male specific part of Y (NPY) contains several genes and gene families. On the short arm (NPYp), there are single-copy genes: Prssly, Teyorf1, Uba1y, Smcy/Kdm5d, Eif2s3y, Uty, Dby/Ddx3y, Usp9y, Sry, duplicated gene Zfy (Zfy1 and 2), duplicated gene H2al2y, and a multi-copy gene Rbmy. The non-pairing region of the long arm (NPYq), representing ~90% of all NPY, contains mostly repetitive sequences, and encodes multiple copies of 5 distinct genes that are expressed in spermatids: Ssty1 and Ssty2, Sly, Srsy, Rbm31y [6]. Y*X is an X chromosome derivative encoding PAR, X centromere and near centromeric region. Sxra is a sex reversal variant Tp(Y)1CtSxr-a encoding almost intact NPYp complement but with Rbmy gene family reduced. Sxrbis a Sxra derivative with a 1.3 Mb deletion that has removed the majority of the NPYp gene complement and created a Zfy2/1 fusion gene. (B) The mice used in this study and their Y chromosome contribution. The X chromosome located Eif2s3y and autosomally located Sry transgenes, are shown in light blue frames. The Zfy2 transgene, shown in brown frame, is located on the X chromosome in the Hrpt locus in close proximity to the Eif2s3y transgene. The genotype designations without the Zfy2 transgene are shown above the diagrammatic representation of sex chromosomes and with the Zfy2 transgene below them (brown font). Sxra and Sxrb gene content is shown in A. n/a = mice with transgenic Zfy2 addition were either not produced or not examined in this study.
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pgen.1005476.g001: Mouse X and Y chromosomes, variant sex chromosomes, and mouse genotypes relevant to this study.(A) The mouse Y chromosome contains ~90 Mb of male specific DNA and ~0.7 Mb constituting the pseudoautosomal region (PAR) situated at the end of the long arm. The PAR is the region of homology with the X that mediates pairing and recombination between the X and Y in normal males. The remaining non-pairing male specific part of Y (NPY) contains several genes and gene families. On the short arm (NPYp), there are single-copy genes: Prssly, Teyorf1, Uba1y, Smcy/Kdm5d, Eif2s3y, Uty, Dby/Ddx3y, Usp9y, Sry, duplicated gene Zfy (Zfy1 and 2), duplicated gene H2al2y, and a multi-copy gene Rbmy. The non-pairing region of the long arm (NPYq), representing ~90% of all NPY, contains mostly repetitive sequences, and encodes multiple copies of 5 distinct genes that are expressed in spermatids: Ssty1 and Ssty2, Sly, Srsy, Rbm31y [6]. Y*X is an X chromosome derivative encoding PAR, X centromere and near centromeric region. Sxra is a sex reversal variant Tp(Y)1CtSxr-a encoding almost intact NPYp complement but with Rbmy gene family reduced. Sxrbis a Sxra derivative with a 1.3 Mb deletion that has removed the majority of the NPYp gene complement and created a Zfy2/1 fusion gene. (B) The mice used in this study and their Y chromosome contribution. The X chromosome located Eif2s3y and autosomally located Sry transgenes, are shown in light blue frames. The Zfy2 transgene, shown in brown frame, is located on the X chromosome in the Hrpt locus in close proximity to the Eif2s3y transgene. The genotype designations without the Zfy2 transgene are shown above the diagrammatic representation of sex chromosomes and with the Zfy2 transgene below them (brown font). Sxra and Sxrb gene content is shown in A. n/a = mice with transgenic Zfy2 addition were either not produced or not examined in this study.
Mentions: We recently investigated spermatogenesis progression and germ cell function in male mice with significantly abrogated Y chromosome complements [5]. We have shown that males with the Y chromosome contribution provided by two transgenes, the testis determinant Sry and the spermatogonial proliferation factor Eif2s3y (Fig 1B, XEOSry and XEY*XSry) have meiotic and postmeiotic arrest, the rare spermatids present in the testes do not elongate, and sperm are not formed. When round spermatids from these males were injected into the oocytes, live mouse progeny were obtained. The success of round spermatid injection (ROSI) was low, with less than 10% of transplanted embryos developing to live offspring. Interestingly, when the Sry transgene was replaced with the Y chromosome derived sex reversal factor Sxrb, encoding for Sry, H2al2y, Prssly, Teyorf1, Rbmy gene cluster, and Zfy2/1 fusion gene (Fig 1A, Sxrb) the resulting males (Fig 1B, XESxrbO and XESxrbY*X) had more advanced spermatid development with clear elongation of these cells, occasional appearance of sperm, and increased ROSI efficiency.

Bottom Line: Spermatogenesis is a key developmental process allowing for a formation of a mature male gamete.During its final phase, spermiogenesis, haploid round spermatids undergo cellular differentiation into spermatozoa, which involves extensive restructuring of cell morphology, DNA, and epigenome.Therefore, only three Y chromosome genes, Sry, Eif2s3y and Zfy2, constitute the minimum Y chromosome complement compatible with successful intracytoplasmic sperm injection in the mouse.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biogenesis Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.

ABSTRACT
Spermatogenesis is a key developmental process allowing for a formation of a mature male gamete. During its final phase, spermiogenesis, haploid round spermatids undergo cellular differentiation into spermatozoa, which involves extensive restructuring of cell morphology, DNA, and epigenome. Using mouse models with abrogated Y chromosome gene complements and Y-derived transgene we identified Y chromosome encoded Zfy2 as the gene responsible for sperm formation and function. In the presence of a Zfy2 transgene, mice lacking the Y chromosome and transgenic for two other Y-derived genes, Sry driving sex determination and Eif2s3y initiating spermatogenesis, are capable of producing sperm which when injected into the oocytes yield live offspring. Therefore, only three Y chromosome genes, Sry, Eif2s3y and Zfy2, constitute the minimum Y chromosome complement compatible with successful intracytoplasmic sperm injection in the mouse.

Show MeSH