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Mutations in non-muscle myosin 2A disrupt the actomyosin cytoskeleton in Sertoli cells and cause male infertility.
- Source :
-
Developmental biology [Dev Biol] 2021 Feb; Vol. 470, pp. 49-61. Date of Electronic Publication: 2020 Nov 12. - Publication Year :
- 2021
-
Abstract
- Mutations in non-muscle myosin 2A (NM2A) encompass a wide spectrum of anomalies collectively known as MYH9-Related Disease (MYH9-RD) in humans that can include macrothrombocytopenia, glomerulosclerosis, deafness, and cataracts. We previously created mouse models of the three mutations most frequently found in humans: R702C, D1424N, and E1841K. While homozygous R702C and D1424N mutations are embryonic lethal, we found homozygous mutant E1841K mice to be viable. However the homozygous male, but not female, mice were infertile. Here, we report that these mice have reduced testis size and defects in actin-associated junctions in Sertoli cells, resulting in inability to form the blood-testis barrier and premature germ cell loss. Moreover, compound double heterozygous (R702C/E1841K and D1424/E1841K) males show the same abnormalities in testes as E1841K homozygous males. Conditional ablation of either NM2A or NM2B alone in Sertoli cells has no effect on fertility and testis size, however deletion of both NM2A and NM2B in Sertoli cells results in infertility. Isolation of mutant E1841K Sertoli cells reveals decreased NM2A and F-actin colocalization and thicker NM2A filaments. Furthermore, A <superscript>E1841K</superscript> /A <superscript>E1841K</superscript> and double knockout Sertoli cells demonstrate microtubule disorganization and increased tubulin acetylation, suggesting defects in the microtubule cytoskeleton. Together, these results demonstrate that NM2A and 2B paralogs play redundant roles in Sertoli cells and are essential for testes development and normal fertility.<br />Competing Interests: Declaration of competing interest The authors declare no competing or financial interests.<br /> (Published by Elsevier Inc.)
- Subjects :
- Actins metabolism
Actomyosin chemistry
Animals
Blood-Testis Barrier metabolism
Cell Shape
Cytoskeleton metabolism
Infertility, Male pathology
Infertility, Male physiopathology
Male
Mice
Microtubules chemistry
Microtubules metabolism
Microtubules ultrastructure
Myosin Heavy Chains genetics
Nonmuscle Myosin Type IIA genetics
Nonmuscle Myosin Type IIB genetics
Nonmuscle Myosin Type IIB metabolism
Organ Size
Permeability
Point Mutation
Sertoli Cells cytology
Sertoli Cells ultrastructure
Testis pathology
Tubulin metabolism
Actomyosin metabolism
Cytoskeleton ultrastructure
Infertility, Male genetics
Myosin Heavy Chains metabolism
Nonmuscle Myosin Type IIA metabolism
Sertoli Cells physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-564X
- Volume :
- 470
- Database :
- MEDLINE
- Journal :
- Developmental biology
- Publication Type :
- Academic Journal
- Accession number :
- 33188738
- Full Text :
- https://doi.org/10.1016/j.ydbio.2020.11.003