Gtpbp2 is required for BMP signaling and mesoderm patterning in Xenopus embryos

Abstract

Smad proteins convey canonical intracellular signals for activated receptors in the TGFβ superfamily, but the activity of Smads and their impact on target genes is further regulated by a wide variety of cofactors and partner proteins. We have identified a new Smad1 partner, a GTPase named Gtpbp2 that is a distant relative of the translation factor eEf1a. Gtpbp2 affects canonical signaling in the BMP branch of the TGFβ superfamily, as morpholino knockdown of Gtpbp2 decreases, and overexpression of Gtpbp2 enhances, animal cap responses to BMP4. During Xenopus development, gtpbp2 transcripts are maternally expressed and localized to the egg animal pole, and partitioned into the nascent ectodermal and mesodermal cells during cleavage and early gastrulation stages. Subsequently, gtpbp2 is expressed in the neural folds, and in early tadpoles undergoing organogenesis gtpbp2 is expressed prominently in the brain, eyes, somites, ventral blood island and branchial arches. Consistent with its expression, morpholino knockdown of Gtpbp2 causes defects in ventral-posterior germ layer patterning, gastrulation and tadpole morphology. Overexpressed Gtpbp2 can induce ventral-posterior marker genes and localize to cell nuclei in Xenopus animal caps, highlighting its role in regulating BMP signaling in the early embryo. Here, we introduce this large GTPase as a novel factor in BMP signaling and ventral-posterior patterning.

Noggin-Mediated Retinal Induction Reveals a Novel Interplay Between Bone Morphogenetic Protein Inhibition, Transforming Growth Factor β, and Sonic Hedgehog Signaling

“…To verify the activation state of the BMP signaling cascade in the different experimental conditions, we analyzed the expression of two genes known to be direct transcriptional targets of this pathway, Ventx1 and Tbx3/ET . As expected, both genes showed consistent expression profiles, being dose‐dependently downregulated by the treatment with the different Noggin1 doses.…”

Identification of mutation in GTPBP2 in patients of a family with neurodegeneration accompanied by iron deposition in the brain

“…Publications relating to this protein and its gene are not numerous. Although GTPBP1 and GTPBP2 are homologous (~45% amino acid sequence identity), the two proteins appear to have non-overlapping functions (Kirmizitas et al, 2014;Woo et al, 2011). In mice, GTPBP1 enhances exosome-mediated mRNA turnover and perhaps also 3′-UTR mediated mRNA degradation.…”

“…While GTPBP2 does not have these roles, it was reported that this protein can stabilize reporter mRNA (Woo et al, 2011). More recently, empirical evidence in support of essential functions for the C-terminus of GTPBP2 that is deleted in the truncated protein of DS-100 patients was reported (Kirmizitas et al, 2014). It was shown that GTPBP2 has roles not shared with GTPBP1 in BMP signaling in Xenopus embryos and that these roles are mediated by direct interaction between the C-terminus of GTPBP2 with Smad1.…”

Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2

“…His-tagged full-length human GTPBP1 and GTPBP2; truncated GTPBP1 152-669 , GTPBP1 152-586 , and GTPBP2 164-602 lacking the N-terminal and C-terminal extensions; and GTPBP2 89-602 corresponding to the translation product that initiates at a downstream AUG codon (suggested to be the active form of the protein) ( Fig. 1A; Kirmizitas et al 2014) were expressed in Escherichia coli (Fig. 1B).…”

“…GTPBP2 mutations have been linked to neurodegeneration in humans as well (Jaberi et al 2016). However, in Xenopus embryos, GTPBP2 was reported to bind to the transcription modulator SMAD1 and take part in BMP/ SMAD1 signaling (Kirmizitas et al 2014) as well as interact with Axin and act as a positive regulator of Wnt signaling (Gillis et al 2016).…”