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HP1gamma function is required for male germ cell survival and spermatogenesis.

Brown JP, Bullwinkel J, Baron-Lühr B, Billur M, Schneider P, Winking H, Singh PB - Epigenetics Chromatin (2010)

Bottom Line: While targeting the Cbx3 gene (encoding the HP1gamma protein) with a conditional targeting vector, we generated a hypomorphic allele (Cbx3hypo), which resulted in much reduced (barely detectable) levels of HP1gamma protein.Adult males exhibit a severe hypogonadism that is associated with a loss of germ cells, with some seminiferous tubules retaining only the supporting Sertoli cells (Sertoli cell-only phenotype).The Cbx3hypo/hypo spermatogenesis defect is similar to that found in Miwi2 and Dnmt3L mutants.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunoepigenetics, Department of Immunology and Cell Biology, Research Center Borstel, D-23845 Borstel, Germany. psingh@fz-borstel.de.

ABSTRACT

Background: HP1 proteins are conserved components of eukaryotic constitutive heterochromatin. In mammals, there are three genes that encode HP1-like proteins, termed HP1alpha, HP1beta and HP1gamma, which have a high degree of homology This paper describes for the first time, to our knowledge, the physiological function of HP1gamma using a gene-targeted mouse.

Results: While targeting the Cbx3 gene (encoding the HP1gamma protein) with a conditional targeting vector, we generated a hypomorphic allele (Cbx3hypo), which resulted in much reduced (barely detectable) levels of HP1gamma protein. Homozygotes for the hypomorphic allele (Cbx3hypo/hypo) are rare, with only 1% of Cbx3hypo/hypo animals reaching adulthood. Adult males exhibit a severe hypogonadism that is associated with a loss of germ cells, with some seminiferous tubules retaining only the supporting Sertoli cells (Sertoli cell-only phenotype). The percentage of seminiferous tubules that are positive for L1 ORF1 protein (ORF1p) in Cbx3hypo/hypo testes is greater than that for wild-type testes, indicating that L1 retrotransposon silencing is reversed, leading to ectopic expression of ORF1p in Cbx3hypo/hypo germ cells.

Conclusions: The Cbx3 gene product (the HP1gamma protein) has a non-redundant function during spermatogenesis that cannot be compensated for by the other two HP1 isotypes. The Cbx3hypo/hypo spermatogenesis defect is similar to that found in Miwi2 and Dnmt3L mutants. The Cbx3 gene-targeted mice generated in this study provide an appropriate model for the study of HP1gamma in transposon silencing and parental imprinting.

No MeSH data available.


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HP1γ protein expression was dramatically reduced in Cbx3hypo/hypo tissues. Protein expression was reduced to almost undetectable levels in testis, kidney, lung, brain, liver spleen and thymus tissues from the Cbx3hypo/hypomice.
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Figure 3: HP1γ protein expression was dramatically reduced in Cbx3hypo/hypo tissues. Protein expression was reduced to almost undetectable levels in testis, kidney, lung, brain, liver spleen and thymus tissues from the Cbx3hypo/hypomice.

Mentions: A dramatic reduction of HP1γ levels was also observed in the Cbx3hypo/hypo mouse tissues; Western blot analysis revealed that HP1γ levels were reduced to almost undetectable levels in all tissues examined (Figure 3). There was no effect of the Cbx3hypo/hypo mutation on the protein levels of HP1α (see Additional file 3, Figure s3a) and HP1β (see Additional file 3, Figure s3b) or on the same three histone post-translational modifications H4K20ME3, H3K9ME3 and H3K9AC (see Additional file 3, Figures s3c to s3e).


HP1gamma function is required for male germ cell survival and spermatogenesis.

Brown JP, Bullwinkel J, Baron-Lühr B, Billur M, Schneider P, Winking H, Singh PB - Epigenetics Chromatin (2010)

HP1γ protein expression was dramatically reduced in Cbx3hypo/hypo tissues. Protein expression was reduced to almost undetectable levels in testis, kidney, lung, brain, liver spleen and thymus tissues from the Cbx3hypo/hypomice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2877046&req=5

Figure 3: HP1γ protein expression was dramatically reduced in Cbx3hypo/hypo tissues. Protein expression was reduced to almost undetectable levels in testis, kidney, lung, brain, liver spleen and thymus tissues from the Cbx3hypo/hypomice.
Mentions: A dramatic reduction of HP1γ levels was also observed in the Cbx3hypo/hypo mouse tissues; Western blot analysis revealed that HP1γ levels were reduced to almost undetectable levels in all tissues examined (Figure 3). There was no effect of the Cbx3hypo/hypo mutation on the protein levels of HP1α (see Additional file 3, Figure s3a) and HP1β (see Additional file 3, Figure s3b) or on the same three histone post-translational modifications H4K20ME3, H3K9ME3 and H3K9AC (see Additional file 3, Figures s3c to s3e).

Bottom Line: While targeting the Cbx3 gene (encoding the HP1gamma protein) with a conditional targeting vector, we generated a hypomorphic allele (Cbx3hypo), which resulted in much reduced (barely detectable) levels of HP1gamma protein.Adult males exhibit a severe hypogonadism that is associated with a loss of germ cells, with some seminiferous tubules retaining only the supporting Sertoli cells (Sertoli cell-only phenotype).The Cbx3hypo/hypo spermatogenesis defect is similar to that found in Miwi2 and Dnmt3L mutants.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunoepigenetics, Department of Immunology and Cell Biology, Research Center Borstel, D-23845 Borstel, Germany. psingh@fz-borstel.de.

ABSTRACT

Background: HP1 proteins are conserved components of eukaryotic constitutive heterochromatin. In mammals, there are three genes that encode HP1-like proteins, termed HP1alpha, HP1beta and HP1gamma, which have a high degree of homology This paper describes for the first time, to our knowledge, the physiological function of HP1gamma using a gene-targeted mouse.

Results: While targeting the Cbx3 gene (encoding the HP1gamma protein) with a conditional targeting vector, we generated a hypomorphic allele (Cbx3hypo), which resulted in much reduced (barely detectable) levels of HP1gamma protein. Homozygotes for the hypomorphic allele (Cbx3hypo/hypo) are rare, with only 1% of Cbx3hypo/hypo animals reaching adulthood. Adult males exhibit a severe hypogonadism that is associated with a loss of germ cells, with some seminiferous tubules retaining only the supporting Sertoli cells (Sertoli cell-only phenotype). The percentage of seminiferous tubules that are positive for L1 ORF1 protein (ORF1p) in Cbx3hypo/hypo testes is greater than that for wild-type testes, indicating that L1 retrotransposon silencing is reversed, leading to ectopic expression of ORF1p in Cbx3hypo/hypo germ cells.

Conclusions: The Cbx3 gene product (the HP1gamma protein) has a non-redundant function during spermatogenesis that cannot be compensated for by the other two HP1 isotypes. The Cbx3hypo/hypo spermatogenesis defect is similar to that found in Miwi2 and Dnmt3L mutants. The Cbx3 gene-targeted mice generated in this study provide an appropriate model for the study of HP1gamma in transposon silencing and parental imprinting.

No MeSH data available.


Related in: MedlinePlus