Defective smooth muscle development in qkI‐deficient mice

Abstract

The qkI gene encodes an RNA binding protein which was identified as a candidate for the classical neurologic mutation, qk v . Although qkI is involved in glial cell differentiation in mice, qkI homologues in other species play important roles in various developmental processes. Here, we show a novel function of qkI in smooth muscle cell differentiation during embryonic blood vessel formation. qkI null embryos died between embryonic day 9.5 and 10.5. Embryonic day 9.5 qkI null embryos showed a lack of large vitelline vessels in the yolk sacs, kinky neural tubes, pericardial effusion, open neural tubes and incomplete embryonic turning. Using X-gal and immunohistochemical staining, qkI is first shown to be expressed in endothelial cells and smooth muscle cells. Analyses of qkI null embryos in vivo and in vitro revealed that the vitelline artery was too thin to connect properly to the yolk sac, thereby preventing remodeling of the yolk sac vasculature, and that the vitelline vessel was deficient in smooth muscle cells. Addition of QKI and platelet-endothelial cell adhesion molecule-1 positive cells to an in vitro para-aortic splanchnopleural culture of qkI null embryos rescued the vascular remodeling deficit. These data suggest that QKI protein has a critical regulatory role in smooth muscle cell development, and that smooth muscle cells play an important role in inducing vascular remodeling.

Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype

“…Despite the developmental defects observed in the vasculature of QkI-deficient embryos, [7][8][9] no studies to date have investigated a role for this RNA-binding protein in VSMCs of the adult vasculature. Therefore, we assessed the levels of QKI expression in human healthy and restenotic atherectomy specimens immunohistochemically.…”

“…5,6 Importantly, QkI null mice are embryonic-lethal because of an inability of immature mural cells to migrate and differentiate into vascular smooth muscle cells (VSMCs) effectively, resulting in perturbed investment and stabilization of nascent vessels in the yolk sac vasculature. [7][8][9] In adults, VSMCs of the artery wall contract and provide vascular tone. 10 However, in response to vascular injury, VSMCs can dedifferentiate from a contractile to a synthetic state.…”

Developmental genetics of the mouse <i>t</i>-complex

“…QKI is believed to regulate pre-mRNA splicing (Wu et al, 2002), mRNA stability (Li et al, 2000;Larocque et al, 2005), nuclear mRNA export (Larocque et al, 2002) and translation repression (Saccomanno et al, 1999). Homozygotes of N-ethyl-N-nitrosourea (ENU)-mutagenized or targeted deficient alleles exhibit a deficiency of vasculogenesis in the yolk sac and die at around embryonic day (E)10.5 (Noveroske et al, 2002;Li et al, 2003). Furthermore, a recent report demonstrated that QKI plays an important role in cancer suppression through stabilization of a microRNA (Chen et al, 2012).…”

Structure–function studies of STAR family Quaking proteins bound to their in vivo RNA target sites

“…In mice, there are three main Qki splice isoforms (QKI-5, QKI-6, and QKI-7), and reduced expression of QKI-6 and QKI-7 isoforms leads to defective maturation of myelinating cells of the CNS (Zearfoss et al 2008), while Qkinull mutations cause neural tube and vascular defects and are embryonic-lethal (Li et al 2003). Low expression levels of human QKI in the CNS have been linked to the development of diseases such as ataxia and schizophrenia as well as the formation of glioblastomas through only partially defined mechanisms (Chenard and Richard 2008).…”