Hmga1/Hmga2 double knock-out mice display a “superpygmy” phenotype

Abstract

The HMGA1 and HMGA2 genes code for proteins belonging to the High Mobility Group A family. Several genes are negatively or positively regulated by both these proteins, but a number of genes are specifically regulated by only one of them. Indeed, knock-out of the Hmga1 and Hmga2 genes leads to different phenotypes: cardiac hypertrophy and type 2 diabetes in the former case, and a large reduction in body size and amount of fat tissue in the latter case. Therefore, to better elucidate the functions of the Hmga genes, we crossed Hmga1-null mice with mice null for Hmga2. The Hmga1−/−/Hmga2−/− mice showed reduced vitality and a very small size (75% smaller than the wild-type mice); they were even smaller than pygmy Hmga2-null mice. The drastic reduction in E2F1 activity, and consequently in the expression of the E2F-dependent genes involved in cell cycle regulation, likely accounts for some phenotypic features of the Hmga1−/−/Hmga2−/− mice.

Hmga1null mouse embryonic fibroblasts display downregulation of spindle assembly checkpoint gene expression associated to nuclear and karyotypic abnormalities

“…Moreover, as already reported 8 and as suggested by the observation of MEFs in culture ( Fig. 2C), we found that the growth rate of Hmga1 ¡/¡ MEFs was much lower than that of the WT counterpart (Fig.…”

“…Since these genes are involved in the regulation of the cell cycle 8 in MEFs, we have evaluated Bub1, Bub1b, Mad2l1 and Ttk expression by qRT-PCR and western blotting in Hmga1 C/C and Hmga1 ¡/¡ MEFs. As shown in Fig.…”

High mobility group (HMG) proteins: Modulators of chromatin structure and DNA repair in mammalian cells

“…Studies of cellular gene transcription expression profiles have demonstrated that while the HMGA1 and HMGA2 proteins regulate transcription of many of the same genes in vivo (and, hence, can somewhat complement the activity of each other in gene knock-out experiments) each protein sub-family has a distinct regulatory profile not shared by the other [12,14,112,113]. This over-lapping, yet idiosyncratic, pattern of target gene regulation is also reflected in the differing phenotypes of homozygous Hmga1 −/− and Hmga2 −/− knock-out mice.…”

“…Recently Federico et al [113] reported the creation of homozygous double Hmga1/Hmga2 knock-out (double-KO) mice by crossing of selected Hmga1 −/− and Hmga2 −/− stains and careful progeny selection. Due to extremely high levels of embryonic lethality only a few double-KO mice were produced and analyzed.…”

“…These findings clearly demonstrate the biological importance of HMGA proteins in controlling many functions that are essential for embryonic and/or fetal development. They further suggest that the 'superpygmy' phenotype of double-KO mice could result from decreased E2F1 activity that would, in turn, lead to reduced cell growth and, perhaps, embryonic stem cell self-renewal [113].…”