Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Abstract

Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin Aonly knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3′ UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…miR‐9 may also have a role during aging. While miR‐9 can target prelamin A, thereby preventing the expression of progerin in models of Hutchinson‐Gilford progeria syndrome (HPGS) (Jung et al ., 2012), other studies (Olivieri et al ., 2013) and this report have observed that the expression of miR‐9 can increase during senescence. The ability of miR‐9 to downregulate CBX7 expression causing p16 INK4a induction and senescence could therefore provide an explanation for the role of miR‐9 in cancer and aging.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…This figure is proposed according to the results obtained on in vitro and in vivo models of accelerated aging syndromes (Jung et al., 2012, 2014; Mariño et al., 2010; Nissan et al., 2012; Ugalde, Español et al., 2011; Ugalde, Ramsay et al., 2011; Xiong et al., 2015; Yu et al., 2013; Zhang et al., 2017)…”

“…They used mice producing only lamin A ( Lmna LAO/LAO knock‐in mice), prelamin A ( Zmpste24 −/− mice that produce prenylated prelamin A but no mature lamin A), and nonfarnesylated progerin ( Lmna nHG/nHG knock‐in mice, which yield exclusively nonfarnesylated progerin from mutant prelamin A transcripts). They demonstrated that lamin A or prelamin A/progerin was dramatically reduced in the brain compared to lamin C (except of course for Lmna LAO/LAO knock‐in mouse model; Jung et al., 2012). They showed that expression of lamin A or its derivatives (prelamin A and progerin) was restricted to vascular and meningeal cells.…”

“…They identified a brain‐specific miRNA, miR‐9, as the major regulator of lamin A expression in this organ. Using different in vitro models (HeLa cells, wild‐type, and Lmna HG/+ mouse embryonic fibroblasts transfected with miR‐9; Jung et al., 2012), and in vivo models, Lmna plao‐5nt knock‐in mice (in which a 5 nt mutation was introduced into the predicted miR‐9 binding site of prelamin A 3′UTR) and Lmna plao‐utr mice (in which prelamin A 3′UTR was replaced by lamin C 3′UTR; Jung et al., 2014), they demonstrated that miR‐9 regulates lamin A or prelamin A expression in the central nervous system by directly targeting their common 3′UTR on mRNAs. These results were confirmed by Nissan et al.…”

“…They also confirmed the direct targeting of miR‐9 on lamin A 3′UTR using a luciferase reporter assay. Based on this interesting discovery, Fong and colleagues (Jung et al., 2012) hypothesized that an induced ectopic expression of progerin in neurons would lead to neuropathy in vivo . They generated the Lmna HG‐C mouse model , corresponding to the Lmna HG/+ mouse, for which the 3′UTR binding site of miR‐9 in prelamin A transcript was removed.…”