Comparative analysis of developmentally regulated expressions of Gadd45a, Gadd45b, and Gadd45g in the mouse and marmoset cerebral cortex

Abstract

The cerebral cortex is an indispensable region that is involved in higher cognitive function in the mammalian brain, and is particularly evolved in the primate brain. It has been demonstrated that cortical areas are formed by both innate and activity-dependent mechanisms. However, it remains unknown what molecular changes induce cortical expansion and complexity during primate evolution. Active DNA methylation/demethylation is one of the epigenetic mechanisms that can modify gene expression via the methylation/demethylation of promoter regions. Three growth arrest and DNA damage-inducible small nuclear proteins, Gadd45 alpha, beta, and gamma, have been identified as regulators of methylation status. To understand the involvement of epigenetic factors in primate cortical evolution, we started by analyzing expression of these demethylation genes in the developing common marmoset (Callithrix jacchus) and mouse (Mus musculus) brain. In the marmoset brain, we found that cortical expression levels of Gadd45 alpha and gamma were reduced during development, whereas there was high expression of Gadd45 beta in some areas of the adult brain, including the prefrontal, temporal, posterior parietal and insula cortices, which are particularly expanded in greater primates and humans. Compared to the marmoset brain, there were no clear regional differences and constant or reduced Gadd45 expression was seen between juvenile and adult mouse brain. Double staining with a neuronal marker revealed that most Gadd45-expressing cells were NeuN-positive neurons. Thus, these results suggest the possibility that differential Gadd45 expression affects neurons, contributing cortical evolution and diversity.

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

“…Despite strong expression of Gadd45α during different stages of development , most of the basic behaviors analyzed were not significantly compromised by life‐long Gadd45a deficiency (Fig EV1). The functions of the Gadd45 family members are similar, but not identical, and their induction differs depending on physiological conditions and cell types .…”

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

“…Differential GADD45 expression was more diverse in the neocortex than in the allocortex, which suggests that GADD45 expression can be related to areal diversity and evolution of the primate neocortex [Matsunaga et al, 2015]. Notably, GADD45A mutant mice exhibit exencephaly [Hollander et al, 1999].…”

“…Many studies revealed that GADD45 proteins play multiple roles in neural development and plasticity and that active DNA demethylation occurs during the learning process [Ma et al, 2009;Guo et al, 2011]. 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].…”

G 2 /M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph 3 PAu[SC(OR) = NPh], R = Me, Et, and iPr, during zebrafish development

“…Stimulation of p53 expression also leads to DNA damage and results in induction of GADD45 [37]. Interestingly, GADD45 destabilizes the cyclin B1/cdc2 complex in vitro suggesting that it may mediate cyclin B1/cdc2 complex inactivation in vivo [38].…”