Genetic Innovation of Cytoskeletal Proteins for Specialized Functions in the Male Germline

男性种系中具有特殊功能的细胞骨架蛋白的遗传创新

• 批准号: 10534251
• 负责人: Courtney Megan Schroeder
• 金额: $ 24.9万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534251
• 关键词: Acceleration; Actin-Binding Protein; Actins; Amino Acid Substitution; Animals; Antibodies; Automobile Driving; Biochemistry; Biological Assay; Biological Process; Candidate Disease Gene; Cell division; Cytoskeletal Proteins; Cytoskeleton; Defect; Drosophila genome; Drosophila genus; Drosophila inturned protein; Eukaryota; Event; Evolution; Exhibits; Family; Family member; Fertility; Future; Gene Duplication; Gene Family; Gene Proteins; Generations; Genes; Genetic; Histologic; Histology; Infertility; Insecta; Interdisciplinary Study; Knock-out; Knockout Mice; Male Infertility; Mammals; Men' s Role; Microscopy; Microtubules; Modeling; Molecular; Mus; Nuclear; Orthologous Gene; Phenotype; Play; Postdoctoral Fellow; Protein Biochemistry; Protein Family; Proteins; Recording of previous events; Recurrence; Reproduction; Research; Role; Spermatogenesis; Structure; Surveys; System; Testing; Testis; Training; Work; cell motility; comparative genomics; cost; design; fitness; fitness test; fly; genetic signature; innovation; male; male fertility; mammalian genome; member; novel; paralogous gene; pressure; programs; recruit; reproductive; reproductive fitness; skills; sperm cell; tool

PROJECT SUMMARY Cytoskeletal proteins are fundamental in many biological processes among all eukaryotes. Given their essentiality, they are conventionally thought to be highly conserved. However, signatures of genetic innovation in the form of gene-family expansions and accelerated amino-acid substitutions are found among key cytoskeletal family members. Rapid molecular divergence between closely related species is unexpected in conserved protein families and is indicative of an adaptive advantage for sequence innovation. This proposal will investigate the causes and consequences of this dramatic diversification of cytoskeletal proteins. Actin- related proteins (Arps) are one cytoskeletal family that has ancient evolutionary origins yet exhibits recurrent genetic innovation in both mammals and insects. Unlike the well-conserved members of the Arp superfamily, divergent Arps are testis-specific in expression, suggesting they have acquired specialized roles for male reproduction. Yet the biological process that drives their innovation is unknown. The localization of gametic Arps in Drosophila suggests they play roles at germline-specific actin structures. This proposal will address the hypothesis that gametic Arps facilitate the generation of actin structures that are critical for male reproductive fitness. Aim 1 will uncover the function of one gametic Arp found in all Drosophila species, Arp53D, which localizes to two germline actin structures during late spermatogenesis. D. melanogaster, which has many well- established genetic tools and only one gametic Arp, provides an advantageous system in which to investigate the function of a divergent Arp at actin and probe how its structural diversification allows for novel roles. Aim 2 will extend the analysis to mammalian gametic Arps to gain a deeper understanding of the potentially shared biological processes that are driving Arp innovation among multiple phyla. A few pieces of evidence suggest that mammalian gametic Arps play actin regulatory roles, much like Arp53D. Aim 2 will take a comprehensive approach to elucidate their evolutionary histories and localization with respect to actin, while characterizing the male infertility phenotype of one Arp with an established mouse knockout model. Finally, preliminary findings suggest additional cases of rapidly evolving cytoskeletal proteins, beyond Arps, are present in the male germline. Aim 3 will systematically search Drosophila and mammalian genomes for rapid evolution and gene duplications among cytoskeletal proteins that are testis-enriched in expression. This aim will yield additional cases of genetic innovation that will serve as projects in the applicant’s future lab to broadly understand the adaptive sequence plasticity of cytoskeletal proteins and what drives their specialization for male reproduction. To launch this project, the applicant requires training in fertility assays, mouse testis histology and additional evolutionary analyses. She will ultimately use her background in biochemistry to study diversifying cytoskeletal proteins at a mechanistic level.

项目总结