Deletion of the Parkin coregulated gene causes male sterility in the quaking ^viable mouse mutant

Abstract

Quaking viable (qk v ) is a recessive neurological mouse mutation with severe dysmyelination of the CNS and spermiogenesis failure. The molecular lesion in the qk v mutant is a deletion of Ϸ1 Mb on mouse chromosome 17 that alters the expression of the qk gene in oligodendrocytes. Complementation analysis between the qk v mutation and qk mutant alleles generated through chemical mutagenesis showed that the male sterility is a distinctive feature of the qk v allele. This observation suggested that the sperm differentiation defect in qk v is due to the deletion of a gene(s) distinct from qk. Here, we demonstrate that the deletion of Pacrg is the cause of male sterility in the qk v mutant. Pacrg is the mouse homologue of the human PARKIN-coregulated gene (PACRG), which encodes for a protein whose biochemical function remains unclear. We show that Pacrg is highly expressed in the testes in both mice and humans. In addition, the expression pattern of Pacrg during spermiogenesis suggests that it plays a role in sperm differentiation. In support of this hypothesis, we show that transgenic expression of Pacrg in testes restores spermiogenesis and fertility in qk v males. This finding provides the first in vivo evidence, to our knowledge, for the function of Pacrg in a model organism. Immunolocalization experiments on isolated spermatozoa show that the Pacrg protein is present in mature sperm. Remarkably, the mammalian Pacrg protein shares significant sequence similarities with gene products from flagellated protozoans, suggesting that Pacrg may be necessary for proper flagellar formation in many organisms.

Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia

“…A recent study, using a genetic model, has demonstrated that in vivo deletion of PACRG results in male sterility, linking PACRG with sperm differentiation and providing evidence that PARK2 and PACRG may have different roles, as deletion of PARK2 has no impact on male fertility. 25 On the other hand, while deletion of PARK2 is associated with the loss of dopaminergic neurons, expression of PACRG is not necessary for the survival of dopaminergic neurons in the mouse brain. 26,27 These differences may actually be due to tissue restricted expression.…”

The flagellum of Trypanosoma brucei: New tricks from an old dog

“…Similarly, mutations in hydin induce hydrocephalus and studies in T. brucei were among the first to show a specific flagellum function, demonstrating that hydin knockdown leads to defects in the positioning and formation/ stability of the axonemal central pair (Broadhead et al, 2006;Dawe et al, 2007;Lechtreck and Witman, 2007). In another recent work, it was shown that two T. brucei homologues of a gene implicated in male sterility (Lorenzetti et al, 2004), PACRG, are required for outer doublet stability in T. brucei (Fig. 3) (Dawe et al, 2005).…”

Parkin‐co‐regulated gene (PACRG) product interacts with tubulin and microtubules

“…This protein is implicated in the spermatogenesis and male fertility in mouse [5] and in the stable assembly of axonemal outer doublet microtubules in Trypanosoma [6]. Our study of Chlamydomonas PACRG showed that it is densely localized along the flagellar outer doublet microtubules, possibly buried in the microtubule wall [7].…”

“…region of PACRG Blast search showed that the sequences homologous to PACRG are conserved within a wide range of flagellate eukaryotes and C. elegans, suggesting that PACRG plays an important role in the cilia/flagella as suggested by the previous studies [5][6][7] (Fig. 2A).…”

“…Abnormalities in the promoter region of Parkin/Park2 and PACRG are implicated in various human diseases that include leprosy [12,16,17], typhoid and paratyphoid fever [18], and leukemia [19], as well as in male sterility [5] and ParkinsonÕs disease [3,4]. Considering such a wide range of abnormalities for which PACRG may be responsible, PACRG can be involved in some fundamental cellular function.…”