AKAP9 Is Essential for Spermatogenesis and Sertoli Cell Maturation in Mice

Abstract

Mammalian male fertility relies on complex inter-and intracellular signaling during spermatogenesis. Here we describe three alleles of the widely expressed A-kinase anchoring protein 9 (Akap9) gene, all of which cause gametogenic failure and infertility in the absence of marked somatic phenotypes. Akap9 disruption does not affect spindle nucleation or progression of prophase I of meiosis but does inhibit maturation of Sertoli cells, which continue to express the immaturity markers anti-Mullerian hormone and thyroid hormone receptor alpha in adults and fail to express the maturation marker p27 Kip1 . Furthermore, gap and tight junctions essential for blood-testis barrier (BTB) organization are disrupted. Connexin43 (Cx43) and zona occludens-1 are improperly localized in Akap9 mutant testes, and Cx43 fails to compartmentalize germ cells near the BTB. These results identify and support a novel reproductive tissue-specific role for Akap9 in the coordinated regulation of Sertoli cells in the testis.

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function

“…These data suggest that an alteration in Sertoli maturation in Akap9-deleted testes does not precede the progressive loss of spermatogenesis and reduction in the complexity of cell types within the seminiferous tubules of Akap9-deficient mice. Thus, unlike the conclusions of Schimenti et al, 15 our data indicate that the change in Sertoli maturation is a secondary rather than a primary cause of the observed spermatogenesis defects in Akap9-deficient animals.…”

“…Taken together, these observations suggest that recombination and meiotic chromosome synapsis are cytologically normal in mutant germ cells and that failure of these spermatocytes to progress beyond this stage are probably due to other causes, a conclusion also reached by the study in Akap9 mutant mice (Akap9 mei2.5/mei2.5 ), which are globally deficient in Akap9. 15 Finally, the breeding of Akap9 cko heterozygous males to Akap9 cko homozygous females yielded knockout mice close to the expected mendelian ratio (41%, analysis of 183 pups). This finding suggests that AKAP9 is not required for the last stages of spermiation to produce sperm capable of fertilizing the egg.…”

“…The more apical localization of ZO-1 and Cx43 observed in 60-dpp Akap9-deficient mice was similar to that reported in Akap9 mei2.5/mei2.5 mutant animals. 15 The robust staining of Cx43 in the Akap9-deficient testes compared with the corresponding age-matched WT testes may be the result of tubule shrinkage ( Figure 5). …”

“…Physiologic and morphologic analysis, performed only for the Akap9 mei2.5/mei2.5 animals, attributed the infertility to a defect in Sertoli cell maturation. 15 To delineate the role of AKAP9 and its MT-regulating activity in BTB function, we generated mice with conditional and inducible Akap9 deletion for spatiotemporal restriction of Akap9 deficiency and mice with global Akap9 deletion. The BTB, established at postnatal day 15 in mice, 16 separates the mitotic/spermatogonial and meiotic/ spermatocyte compartment and undergoes remodeling at stage VIII of the seminiferous epithelial cell cycle to facilitate the transport of preleptotene spermatocytes across the barrier so that meiosis I/II and subsequent postmeiotic spermatid development can take place in the adluminal compartment behind the BTB.…”

Pharmacological Interference With Protein-protein Interactions of Akinase Anchoring Proteins as a Strategy for the Treatment of Disease

“…Thus targeting AKAP--dependent protein--protein interactions in the nervous system with specific pharmacological agents might be an option for the treatment of neuronal disorders. Oocyte meiosis defects, female infertility (mouse KO) [193] Heart failure (decreased interaction with PKA) [194]; Obesity (reduced gene expression) [96]; HIV replication and infection [146,147] AKAP2 AKAP2 Actin cytoskeleton, apical membrane of epithelial cells N/A Heart failure (increased interaction with PKA) [194]; Kallmann syndrome, bone anomalies (gene disruption) [195] [196] Cardiac myocyte hypertrophy [197]; mAKAP ablation beneficial in heart disease [196] AKAP18α AKAP7 Plasma membrane Normal response to adrenergic stimulation (KD in cardiac myocytes) [40] Heart failure (increased interaction with PKA) [194] AKAP18ɣ Sertoli cell maturation defects in sperm (mouse KO) [201] Heart failure (decreased interaction with PKA) [194]; cardiac arrhythmias and long Q--T syndrome (genetic polymorphism Ser1570Lys) [202]; male infertility (allelic mutations)…”