Conserved patterns of gene expression in mice and goats in the vicinity of the Polled Intersex Syndrome (PIS) locus

Abstract

The PIS mutation is a genomic ~12-kb deletion affecting long-range gene transcription and causing XX sex reversal and hornlessness in goats by simultaneous long-range action on two genes, gPISRT1 and gFOXL2. In this study, a comparative human/mouse analysis of the orthologous region was carriedout, permittingthe targeting of genes in the 1-Mb environment, and identification of previously unknown mouse orthologues for Pisrt1, Bpesc1 and Chr3syt, and a human orthologue for PISRT1. PCR primers were defined and made it possible to analyse tissue-specific gene expression in mice and goats for 10 and 8 genes, respectively. The profile of expression was analysed by principal component analysis (PCA). The results indicate that FAIM (Fas apoptotic inhibitory molecule) is expressed similarly to FOXL2 (the primary determinant of ovary development located 280 kb away from the PIS mutation). However, we could demonstrate in goats that the PIS mutation has no direct effect on FAIM expression. Therefore, FAIM could contribute to normal ovarian function by inhibiting the apoptotic effect of Fas in the ovary but it relies on other regulatory elements.

Disease-Causing 7.4 kb Cis-Regulatory Deletion Disrupting Conserved Non-Coding Sequences and Their Interaction with the FOXL2 Promotor: Implications for Mutation Screening

“…In addition, no expression could be detected in fibroblasts, while a low PISRT1 expression could be observed in KGN cells, indicating a co-expression of PISRT1 and FOXL2 in adult ovarian granulosa cells. These findings are consistent with expression profiles in goat and mice [13]. The latter is in line with a presumed regulatory function of PISRT1 , requiring a tissue and cell-type specific expression.…”

“…This suggests the existence of distinct interspecies cis -regulatory elements, which have similar effects when disrupted. Caprine PISRT1 encodes a long non-coding transcript (ncRNA) of 1.5 kb that is highly expressed in adult testis [13]. A full-length cDNA of 758 bp was identified by 5′ RACE PCR starting from the known testis ESTs containing a polyadenylation site (Figure S1).…”

“…The phenotype is caused by a regulatory 11.7 kb deletion located 280 kb upstream of goat FOXL2 . It was shown that the deletion alters the transcription of at least three genes: FOXL2 , the non-protein coding gene PISRT1 (PIS-regulated transcript 1) (AF404302) and PFOXic (promoter FoxL2 inverse complementary) (AY648048) [13]–[15]. In agreement with the findings in the translocation patients and in the PIS goat, the distant microdeletions found in human BPES were hypothesized to disturb long-range transcriptional control of FOXL2 expression through the disruption of one or more cis -acting regulatory elements.…”

The pathway to femaleness: current knowledge on embryonic development of the ovary

“…The Polled/intersex syndrome (PIS) in goats is a perfect example of this case. Two genes (Pisrti and Foxl2) have been linked to PIS and one of these genes Foxl2, a forkhead transcription factor, emerges as a potential candidate for the "Z" gene (Pailhoux et al, 1994(Pailhoux et al, , 2001(Pailhoux et al, , 2002(Pailhoux et al, , 2003Vaiman et al, 1999;Nikic and Vaiman, 2004;Pannetier et al, 2003).…”

Molecular cloning of doublesex and mab-3-related transcription factor 1, forkhead transcription factor gene 2, and two types of cytochrome P450 aromatase in Southern catfish and their possible roles in sex differentiation

“…Mutation of Foxl2 gives rise to various diseases, such as blepharophimosis-ptosis-epicanthus inversus syndrome and premature ovarian failure in humans as well as polled intersex syndrome (PIS) in goats (Pailhoux et al 2001, Nikic & Vaiman 2004. During early human development, Foxl2 plays a crucial role in female reproduction, especially in differentiation and proliferation of granulosa cells, ovarian development, and maintenance of ovarian function by regulating the transcription of certain target genes , Loffler et al 2003, Pisarska et al 2004, Yao 2005.…”