Cfap97d1 is important for flagellar axoneme maintenance and male mouse fertility

Abstract

The flagellum is essential for sperm motility and fertilization in vivo. The axoneme is the main component of the flagella, extending through its entire length. An axoneme is comprised of two central microtubules surrounded by nine doublets, the nexin-dynein regulatory complex, radial spokes, and dynein arms. Failure to properly assemble components of the axoneme in a sperm flagellum, leads to fertility alterations. To understand this process in detail, we have defined the function of an uncharacterized gene, Cfap97 domain containing 1 (Cfap97d1). This gene is evolutionarily conserved in mammals and multiple other species, including Chlamydomonas. We have used two independently generated Cfap97d1 knockout mouse models to study the gene function in vivo. Cfap97d1 is exclusively expressed in testes starting from post-natal day 20 and continuing throughout adulthood. Deletion of the Cfap97d1 gene in both mouse models leads to sperm motility defects (asthenozoospermia) and male subfertility. In vitro fertilization (IVF) of cumulus-intact oocytes with Cfap97d1 deficient sperm yielded few embryos whereas IVF with zona pellucida-free oocytes resulted in embryo numbers comparable to that of the control. Knockout spermatozoa showed abnormal motility characterized by frequent stalling in the anti-hook position. Uniquely, Cfap97d1 loss caused a phenotype associated with axonemal doublet heterogeneity linked with frequent loss of the fourth doublet in the sperm stored in the epididymis. This study demonstrates that Cfap97d1 is required for sperm flagellum ultra-structure maintenance, thereby playing a critical role in sperm function and male fertility in mice.

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“…In Drosophila, the hemingway gene (hmw) has been identified as a necessary component for motile cilia function. This gene encodes a protein HMW characterized by a highly conserved coiled-coil domains that is also found in the gene products of their human ortholog, KIAA1430 [5] (also known as CFAP97 [8] and in mice ortholog Cfap97d1 (Cfap97 domain containing 1) [9] . Cfap97 and Cfap97d1 gene products in mice contain the coiled-coil domains that we mentioned in the study on Drosophila [5,9] .…”

“…This gene encodes a protein HMW characterized by a highly conserved coiled-coil domains that is also found in the gene products of their human ortholog, KIAA1430 [5] (also known as CFAP97 [8] and in mice ortholog Cfap97d1 (Cfap97 domain containing 1) [9] . Cfap97 and Cfap97d1 gene products in mice contain the coiled-coil domains that we mentioned in the study on Drosophila [5,9] . HMW is conserved in species with motile cilia and, in Drosophila, hmw is expressed in ciliated sensory neurons and spermatozoa [5] , thus we can be expected that CFAP97 be also expressed in human ciliated sensory neurons and spermatozoa.…”

“…The flagellum is essential for motility of spermatozoa in vivo. The axonemal is the main component of flagella and spans its entire length [9] . An axonemal is composed of 2 central microtubules surrounded by 9 doublets (denoted 9+2 in scientific literature), the nexin-dynein regulatory complex, the radial rays, and the dynein arms [9] .…”

“…The axonemal is the main component of flagella and spans its entire length [9] . An axonemal is composed of 2 central microtubules surrounded by 9 doublets (denoted 9+2 in scientific literature), the nexin-dynein regulatory complex, the radial rays, and the dynein arms [9] . Failure to mount correctly axonemal components in a sperm flagellum results in impaired fertility [9] .…”

“…An axonemal is composed of 2 central microtubules surrounded by 9 doublets (denoted 9+2 in scientific literature), the nexin-dynein regulatory complex, the radial rays, and the dynein arms [9] . Failure to mount correctly axonemal components in a sperm flagellum results in impaired fertility [9] . (Fig.1) Oura et al [9] have defined the function of Cfap97d1, an uncharacterized gene in mice.…”