Differential roles of TGIF family genes in mammalian reproduction

Abstract

BackgroundTG-interacting factors (TGIFs) belong to a family of TALE-homeodomain proteins including TGIF1, TGIF2 and TGIFLX/Y in human. Both TGIF1 and TGIF2 act as transcription factors repressing TGF-β signalling. Human TGIFLX and its orthologue, Tex1 in the mouse, are X-linked genes that are only expressed in the adult testis. TGIF2 arose from TGIF1 by duplication, whereas TGIFLX arose by retrotransposition to the X-chromosome. These genes have not been characterised in any non-eutherian mammals. We therefore studied the TGIF family in the tammar wallaby (a marsupial mammal) to investigate their roles in reproduction and how and when these genes may have evolved their functions and chromosomal locations.ResultsBoth TGIF1 and TGIF2 were present in the tammar genome on autosomes but TGIFLX was absent. Tammar TGIF1 shared a similar expression pattern during embryogenesis, sexual differentiation and in adult tissues to that of TGIF1 in eutherian mammals, suggesting it has been functionally conserved. Tammar TGIF2 was ubiquitously expressed throughout early development as in the human and mouse, but in the adult, it was expressed only in the gonads and spleen, more like the expression pattern of human TGIFLX and mouse Tex1. Tammar TGIF2 mRNA was specifically detected in round and elongated spermatids. There was no mRNA detected in mature spermatozoa. TGIF2 protein was specifically located in the cytoplasm of spermatids, and in the residual body and the mid-piece of the mature sperm tail. These data suggest that tammar TGIF2 may participate in spermiogenesis, like TGIFLX does in eutherians. TGIF2 was detected for the first time in the ovary with mRNA produced in the granulosa and theca cells, suggesting it may also play a role in folliculogenesis.ConclusionsThe restricted and very similar expression of tammar TGIF2 to X-linked paralogues in eutherians suggests that the evolution of TGIF1, TGIF2 and TGIFLX in eutherians was accompanied by a change from ubiquitous to tissue-specific expression. The distribution and localization of TGIF2 in tammar adult gonads suggest that there has been an ultra-conserved function for the TGIF family in fertility and that TGIF2 already functioned in spermatogenesis and potentially folliculogenesis long before its retrotransposition to the X-chromosome of eutherian mammals. These results also provide further evidence that the eutherian X-chromosome has actively recruited sex and reproductive-related genes during mammalian evolution.

DAX1/NR0B1 Was Expressed During Mammalian Gonadal Development and Gametogenesis Before It Was Recruited to the Eutherian X Chromosome1

“…Furthermore, it suggests that this role for NR0B1 in Sertoli cell function existed before it was relocated to the X chromosome. This is similar to the pattern observed in other marsupial-autosomal/eutherian X-linked genes, ARX and TGIF [51,52], which both evolved roles in Sertoli cell function and male reproduction before their recruitment to the X chromosome.…”

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

“…Our GO enrichment analysis also showed enrichment of H1T2 ChIP signals at the promoters of genes of several other developmental processes related pathways ( Fig 4A; Additional le 8: Table S8): GO: 0044707~single-multicellular organism process (115 genes); GO: 0048856~anatomical structure development (105 genes); GO: 0044767~single-organism developmental process (106 genes); GO: 0050793~regulation of developmental process (43 genes). Some of the important candidate genes are TWIST2, TGLF1, CNOT3, SMARCC3 and ZFP whose functions in early embryonic differentiation process have been well documented (47)(48)(49)(50)(51).…”

TGIF1 and SF1 polymorphisms are associated with litter size in Small Tail Han sheep

“…TGF-β induced factor homeobox 1 (TGIF1) is a member of the three-amino-acid loop-extension (TALE) superfamily that is highly expressed in human (Hu, Yu, Shaw, Renfree, & Pask, 2011) and…”

“…Indeed, the inhibition or mutation of key members of the TGF-β/SMAD signalling pathway can cause reproductive problems (Chand, Robertson, Shelling, & Harrison, 2007), including sterility (Li et al, 2017). Significantly, TGIF1 in human and zebra fish functions as a repressor, and reversibly modulates important members of the TGF-β/SMAD signalling pathways that are activated by TGF-β, such as SMAD2 and SMAD4 (Hu et al, 2011;Hyman, Bartholin, Newfeld, & Wotton, 2003;Wotton, Lo, Lee, & Massagué, 1999). Therefore, TGIF1 may be a crucial factor in the reproduction of sheep and other mammalian species.…”