Gadd45a and Gadd45g regulate neural development and exit from pluripotency in Xenopus

Abstract

Gadd45 genes encode a small family of multifunctional stress response proteins, mediating cell proliferation, apoptosis, DNA repair and DNA demethylation. Their role during embryonic development is incompletely understood. Here we identified Xenopus Gadd45b, compared Gadd45a, Gadd45b and Gadd45g expression during Xenopus embryogenesis, and characterized their gain and loss of function phenotypes. Gadd45a and Gadd45g act redundantly and double Morpholino knock down leads to pleiotropic phenotypes, including shortened axes, head defects and misgastrulation. In contrast, Gadd45b, which is expressed at very low levels, shows little effect upon knock down or overexpression. Gadd45ag double Morphants show reduced neural cell proliferation and downregulation of pan-neural and neural crest markers. In contrast, Gadd45ag Morphants display increased expression of multipotency marker genes including Xenopus oct4 homologs as well as gastrula markers, while mesodermal markers are downregulated. The results indicate that Gadd45ag are required for early embryonic cells to exit pluripotency and enter differentiation.

MicroRNA-383 Regulates the Apoptosis of Tumor Cells through Targeting Gadd45g

“…Gadd45g has also been shown to promote neuronal differentiation in Xenopus and hEC cells. The knockdown of both Gadd45a and Gadd45g in Xenopus decreases neural crest markers and increases multipotency markers [31]. Gadd45g overexpression in hEC cells elevates neuronal markers, while it down-regulates pluripotency associated genes [39],[47].…”

“…Gadd45g has been reported to be up-regulated after UV irradiation in both normal and tumor cells [26],[27]. In addition, Gadd45 genes are also reported to be involved in the processes of embryonic development and differentiation in several species [28]–[31]. Recently, Gadd45g was implicated in male sex determination by regulating Sry expression [32],[33].…”

Clinical and Molecular Cytogenetic Characterization of a de novo Interstitial 1p31.1p31.3 Deletion in a Boy with Moderate Intellectual Disability and Severe Language Impairment

“…Matsunaga et al [2015] performed a comparative analysis of developmentally regulated expressions of GADD45A, GADD45B and GADD45G in mouse and marmoset cerebral cortex and concluded that GADD45A expression was detected during the neonatal stage but decreased during subsequent development. Furthermore, knockdown of GADD45A or GADD45G expression in Xenopus embryos blocked neural differentiation, and knockdown of both genes synergistically enhanced the phenotype [Kaufmann and Niehrs, 2011]. Furthermore, loss-of-function analyses in mice revealed that both GADD45A and GADD45B are involved in neurite outgrowth [Ma et al, 2009;Sarkisian and Siebzehnrubl, 2012].…”

Gadd45α modulates aversive learning through post‐transcriptional regulation of memory‐related mRNA s

“…D Immunohistochemistry for hemagglutinin (HA, fused to Gadd45a) in Gadd45a-WT (left), Gadd45a-overexpression (middle) and pivotal role in their functions [38]. In fact, studies on the role of Gadd45 proteins during neural development suggest compensatory processes [39]. In this context, it is not surprising that Gadd45a-KO mice display unaltered behavior in most of the tasks analyzed and that Sultan et al observed mostly normal baseline behavioral tasks in Gadd45b-KO mice [12].…”