Abstract
K-ras is essential for embryogenesis and its mutations are involved in human developmental syndromes and cancer. To determine the consequences of K-ras activation in urothelium, we used uroplakin-II (UPK II) promoter driven Cre recombinase mice and generated mice with mutated KrasG12D allele in the urothelium (UPK II-Cre;LSL-K-rasG12D). The UPK II-Cre;LSL-K-rasG12D mice died neonatally due to lung morphogenesis defects consisting of simplification with enlargement of terminal air spaces and dysmorphic pulmonary vasculature. A significant alteration in epithelial and vascular basement membranes, together with fragmentation of laminin, points to extracellular matrix degradation as the causative mechanism of alveolar and vascular defects. Our data also suggest that altered protease activity in amniotic fluid might be associated with matrix defects in lung of UPK II-Cre;LSL-K-rasG12. These defects resemble those observed in early stage human neonatal bronchopulmonary dysplasia (BPD), although the relevance of this new mouse model for BPD study needs further investigation.
Highlights
Ras proteins, a super-family of cell membrane GTPases, are key regulators of pathways involved in cell survival, proliferation and differentiation [1]
UPK II-Cre expression is restricted to urothelium A transgenic mouse that expressed the Cre recombinase enzyme in bladder epithelium was generated by utilizing the urothelium specific promoter uroplakin II (UPK II)
To confirm urotheliumrestricted expression of the UPK II-Cre mice, a reporter strain was obtained by breeding the UPK II-Cre with Rosa-R26R-YFP floxed mice
Summary
A super-family of cell membrane GTPases, are key regulators of pathways involved in cell survival, proliferation and differentiation [1]. Activating somatic point mutations of Ras are very frequent in cancer [2]. Some recent studies have demonstrated that germline Ras mutations play a role in a sub-group of developmental disorders collectively known as neuro-facial-cardiocutaneous syndromes [3]. Oncogenic Ras somatic mutations stabilize the GTP-bound conformation of the protein, constitutively activating their effector pathways and their biological effects being dependent upon the type of mutation and the cellular context [6]. Mutations found in developmental disorders [7] are activating mutations, and the widespread expression of mutated K-rasG12D allele in the embryos is lethal due to impaired placental function [8] including heart and brain development defects [9]. Its conditional expression in epithelia causes hyperplasia and dysplasia, sometimes leading to carcinomas [9]
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