Biology subjects

Ambros, V.

Publications and source records attributed to Ambros, V..

3 recordsLinked to original sources

bioRxiv2018

Trans-splicing of the C. elegans let-7 primary transcript developmentally regulates let-7 microRNA biogenesis and let-7 family microRNA activity

let-7 is a microRNA whose sequence and roles as a regulator of developmental progression are conserved throughout bilaterians. In most systems, transcription of the let-7 locus occurs relatively early in development, whilst processing of let-7 primary transcript into mature microRNA arises later and is associated with cellular differentiation. In C. elegans and other animals, the RNA binding protein LIN-28 post-transcriptionally inhibits let-7 biogenesis at early developmental stages. The mechanisms by which LIN-28 and other factors developmentally regulate let-7 biogenesis are not fully understood. Nor is it understood how the developmental regulation of let-7 might influence the expression or activities of other microRNAs of the same seed family. Here we show that in C. elegans, the primary let-7 transcript (pri-let-7) is trans-spliced to SL1 splice leader at a position downstream of the let-7 precursor stem-loop, producing a short, polyadenylated downstream mRNA. The trans-splicing event negatively impacts the biogenesis of mature let-7 microRNA in cis, likely by destabilizing the upstream pri-let-7 fragment. Moreover, the trans-spliced downstream mRNA contains complimentary sequences to multiple members of the let-7 seed family (let-7fam), and thereby serves as a sponge to negatively regulate let-7fam function in trans. Thus, this study provides evidence for a mechanism by which splicing of a microRNA primary transcript can negatively regulate said microRNA in cis as well as other microRNAs in trans.\n\nHIGHLIGHTSO_LIThe let-7 primary transcript is trans-spliced to produce an RNA that functions as a sponge that negatively regulates the let-7-family microRNAs.\nC_LIO_LITrans-splicing of this RNA negatively impacts let-7 microRNA biogenesis.\nC_LIO_LILIN-28 regulates this trans-splicing event\nC_LI

molecular biology↗

bioRxiv2018

The C. elegans heterochronic gene lin-28 coordinates the timing of hypodermal and somatic gonadal programs for hermaphrodite reproductive system morphogenesis

C. elegans heterochronic genes determine the timing of expression of specific cell fates in particular stages of developing larva. However, their broader roles in coordinating developmental events across diverse tissues has been less well investigated. Here, we show that loss of lin-28, a central heterochronic regulator of hypodermal development, causes reduced fertility associated with abnormal somatic gonad morphology. In particular, the abnormal spermatheca-uterine valve morphology of lin-28(lf) hermaphrodites trap embryos in the spermatheca, which disrupts ovulation and causes embryonic lethality. The same genes that act downstream of lin-28 in the regulation of hypodermal developmental timing also act downstream of lin-28 in somatic gonad morphogenesis and fertility. Importantly, we find that hypodermal expression, but not somatic gonadal expression, of lin-28 is sufficient for restoring normal somatic gonad morphology in lin-28(lf) mutants. We propose that the abnormal somatic gonad morphogenesis of lin-28(lf) hermaphrodites results from temporal discoordination between the accelerated hypodermal development and normally timed somatic gonad development. Thus, our findings exemplify how a cell-intrinsic developmental timing program can also control cell non-autonomous signaling critical for proper development of other interacting tissues.

developmental biology↗

bioRxiv2016

A microRNA family exerts maternal control on sex determination in C. elegans

Gene expression in early animal embryogenesis is in large part controlled post-transcriptionally. Maternally-contributed microRNAs may therefore play important roles in early development. We have elucidated a major biological role of the nematode mir-35 family of maternally-contributed, essential microRNAs. We show that this microRNA family regulates the sex determination pathway at multiple levels, acting both upstream and downstream of her-1 to prevent aberrantly activated male developmental programs in hermaphrodite embryos. The predicted target genes that act downstream of the mir-35 family in this process, sup-26 and nhl-2, both encode RNA binding proteins, thus delineating a previously unknown post-transcriptional regulatory subnetwork within the well-studied sex determination pathway of C. elegans. Genome-wide profiling of SUP-26 binding targets reveals 775 mRNAs, most of which have no known role in sex determination, suggesting that the mir-35 family may modulate numerous other pathways via regulation of sup-26. Since sex determination in C. elegans requires zygotic gene expression to read the sex chromosome karyotype, early embryos must remain gender-naive; our findings show that the mir-35 family microRNAs act in the early embryo to function as a developmental timer that preserves naivete and prevents premature deleterious developmental decisions.

developmental biology↗