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Sex Differences in Response of the Bovine Embryo to Colony

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Sex Differences in Response of the Bovine Embryo to Colony REPRODUCTIONRESEARCH A-kinase anchoring protein 4 has a conserved role in mammalian spermatogenesis Yanqiu Hu, Hongshi Yu, Andrew J Pask, Deborah A O’Brien1, Geoff Shaw and Marilyn B Renfree ARC Centre of Excellence for Kangaroo Genomics, Department of Zoology, The University of Melbourne, Melbourne, Victoria 3010, Australia and 1Department of Cell & Developmental Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7090, USA Correspondence should be addressed to M B Renfree; Email: [email protected] Abstract A-kinase anchor protein 4 (AKAP4) is an X-linked member of the AKAP family of scaffold proteins that anchor cAMP-dependent protein kinases and play an essential role in fibrous sheath assembly during spermatogenesis and flagellar function in spermatozoa. Marsupial spermatozoa differ in structural organization from those of eutherian mammals but data on the molecular control of their structure and function are limited. We therefore cloned and characterized the AKAP4 gene in a marsupial, the tammar wallaby (Macropus eugenii). The gene structure, sequence, and predicted protein of AKAP4 were highly conserved with that of eutherian orthologues and it mapped to the marsupial X-chromosome. There was no AKAP4 expression detected in the developing young. In the adult, AKAP4 expression was limited to the testis with a major transcript of 2.9 kb. AKAP4 mRNA was expressed in the cytoplasm of round and elongated spermatids while its protein was found on the principal piece of the flagellum in the sperm tail. This is consistent with its expression in other mammals. Thus, AKAP4 appears to have a conserved role in spermatogenesis for at least the last 166 million years of mammalian evolution. Reproduction (2009) 137 645–653 Introduction of the sperm fibrous sheath in all mammals so far examined (Carrera et al. 1994, 1996, Fulcher et al. 1995, The sperm tail controls sperm motility and effective sperm Turner et al. 1998, Colledge & Scott 1999, Eddy et al. delivery, and also aids in penetration of the oocyte which 2003). AKAP4 anchors cAMP-dependent protein kinase is essential for fertilization (Miki et al. 2002). It is made up A (PKA) to the fibrous sheath of the spermatozoon where of the connecting, middle, principal, and end piece. The the kinase is likely to be required for the regulation of principal piece occupies approximately three quarters of spermatozoal motility (Edwards & Scott 2000, Brown the length of the flagellum and acts as the main structure driving sperm motility. The fibrous sheath is a unique et al. 2003). Its protein is restricted to the spermatogenic cytoskeletal structure surrounding the axoneme and the cells from the round spermatid stage until spermatozoa outer dense fibers in the principal piece of the flagellum mature. Akap4 mRNA is expressed only in the post- and is largely comprised of A-kinase anchor proteins meiotic phase of spermatogenesis (Miki et al. 2002). (AKAPs) and a sperm-specific isozyme of glyceraldehyde Since it is present only in germ cells and not in the 3-phosphate dehydrogenase (GAPDHS; Bunch et al. somatic cells of the testis or in any other tissues (Fulcher 1998, Mandal et al. 1999, Vijayaraghavan et al. 1999, et al. 1995), AKAP4 was thought to be a scaffold protein Brown et al.2003). During sperm maturation and involved in regulating flagellum function (Miki et al. capacitation many changes occur including modification 2002). Akap4 deletion results in shorter sperm flagellum of the mitochondria matrix and the mid-piece differen- and an incomplete fibrous sheath formation causing tiation necessary for motility in marsupials (Temple-Smith infertility due to loss of motility (Miki et al. 2002). AKAP4 & Bedford 1976). GAPDHS was identified as a conserved interacts with a number of other proteins in the fibrous mammalian energy source for sperm motility in marsu- sheath. One of these is AKAP3, another important pials (Ricci & Breed 2005). All of these data suggest that component of the fibrous sheath (Mandal et al. 1999, marsupials employ the same molecular strategies as Vijayaraghavan et al. 1999, Brown et al. 2003). In Akap4 eutherians during spermatogenesis. null mice, the amount of AKAP3 was reduced both in AKAP4,anX-linked member of the AKAP gene family testis and sperm (Miki et al. 2002) suggesting a functional (Turner et al. 1998) encodes the most abundant protein link in the recruitment of these two proteins. q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-08-0337 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/28/2021 10:38:53AM via free access 646 Y Hu and others GAPDHS is another major fibrous sheath protein that & Rodger 1999). Once in the female tract, the T-shape is is essential for glycolysis providing an energy source for resumed (Bedford & Breed 1994). While the marsupial sperm motility. It is also distributed in the principal piece sperm head has become more compact but there is no of the sperm flagellum (Bunch et al. 1998). While special stability of chromatin in the nucleus by disulphide GAPDHS is present in Akap4 null mice, it does not bonding or in its head membranes (Temple-Smith & accumulate in the flagellum (Miki et al. 2002). Therefore, Bedford 1976, Cummins 1980), and although cAMP sperm motility is still disrupted in the absence of Akap4 induces tyrosine phosphorylation of sperm proteins, it is due to the interference with signal transduction and lack not yet known whether capacitation occurs in marsupials of association of glycolytic enzymes (Miki et al. 2002, (Sidhu et al. 2004). These differences in structural Brown et al. 2003). organization suggest that there may be differences in the The fibrous sheath is a conserved structure that genes controlling spermatogenesis and sperm function surrounds the outer dense fibers of the principal piece and motility. There has as yet been no study of the AKAP region of the sperm flagellum in both marsupial and genes and proteins in marsupials. Given the importance eutherian mammals (Eddy 2007). Besides AKAP4, AKAP3 of AKAP4 for sperm function in eutherian mammals, this and GAPDHS, many other proteins are located on the study examined the conservation of AKAP4 sequences in flagellum. At least 17 major proteins have been identified marsupials and a monotreme, and examined its in the fibrous sheath in rats (Kim et al.1995b), 14 in expression during spermatogenesis in a marsupial, the humans (Jassim et al. 1992), and 10 in rabbits (Kim et al. tammar wallaby M. eugenii. 1995b, 1997). The amino acid composition of the purified fibrous sheath from human, rabbit, and rat spermatozoa are similar, indicating that mammalian sperm tail fibrous Results sheaths are composed of similar types of proteins (Kim et al. 1997). The outer dense fibers, another specific Cloning and characterization of the tammar AKAP4 cytoskeletal component in mammals, encompasses the gene axoneme in the middle and principal pieces of the sperm An w2.5 kb partial AKAP4 cDNA sequence was obtained tail, cooperating with the fibrous sheath to participate in with cross-species primers from adult tammar testis cDNA. signaling pathways to regulate sperm stability and motility. The full length cDNA was obtained with RACE. Sequence The genes that encode bovine and porcine outer dense comparison with tammar partial genomic sequence fiber one proteins are highly conserved with those of (obtained from the trace archives at NCBI; (http://www. human and rat (Kim et al.1995a). In a marsupial (the ncbi.nlm.nih.gov/) confirmed the locations of all six exons, brushtail possum Trichosurus vulpecula), there are seven consistent with the genomic structure in human, mouse, major proteins in the outer dense fibers and 12 major and opossum. The full-length cDNA encodes a protein of proteins in the fibrous sheath (Ricci & Breed 2001). There is 850 amino acids (Fig. 1) with exon 5 (the largest, about also strong cross-reactivity to the brushtail possum fibrous 2.2 kb) encoding the mature protein (Fig. 2A). sheath proteins in the principal piece of the koala Amino acid alignment demonstrates that AKAP4 is Phascolartcos cinereus, the dunnart Sminthopsis macro- highly conserved among the mammals. The entire wallaby ura, and the tammar wallaby Macropus eugenii as well as AKAP4 protein shares 93.4% amino acid similarity with in that of the rat (Ricci & Breed 2001). Several other opossum (another marsupial), 80.0% with platypus spermatozoon-specific proteins have been isolated from (monotreme), 80.8% with human, 84.3% with mouse, marsupial sperm. Two tammar sperm proteins, PSA-10 and 84.4% with rat, 86.7% with dog, 84.6% with cow, and WSA-1 (Harris & Rodger 1998, 2005) are present on the 80.5% with horse. The cyclic AMP-dependent PKA plays a acrosome, midpiece, and principal piece of mature central role in sperm capacitation, motility and in the spermatozoa but as yet nothing is known of their function acrosome reaction. Two tethering domains of PKA, type Ia (Harris & Rodger 1998, 2005). regulatory subunit (RIa), and type IIa regulatory subunit Although the 14 stages of spermiogenesis recognized in (RIIa), are highly conserved in all AKAP4 proteins (Fig. 1). the tammar and sperm maturation follow a generally Protein tyrosine phosphorylation is one of the most similar pattern to that of eutherians (Tyndale-Biscoe & important regulatory pathways to modulate events associ- Renfree 1987, Harris & Rodger 2005), the process in ated with sperm function, and conserved tyrosine sites marsupials is complicated and dynamic and differs in have been found across all AKAP4 proteins (Fig. 1). some respects from that of eutherians (Lin et al. 1997). Phylogenetic analysis with PHYLIP 3.63 groups AKAP4 Sperm of most marsupials have a dorso-ventrally flattened proteins into the same three main clusters using three nuclear surface (Temple-Smith 1994) and there is a more different methods (maximum-likelihood, maximum parsi- stable acrosome on the dorsal nuclear surface (Mate & mony, and neighbor-joining; only neighbor-joining tree Rodger 1991, Sistina et al.
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