LGL1, a novel branching morphogen in developing kidney, is induced by retinoic acid

Abstract

Late-gestation lung protein 1 (LGL1) is a glycoprotein secreted by fetal lung mesenchyme that stimulates branching morphogenesis of the developing lung bud. We show that Lgl1 mRNA and protein are also expressed in mesenchymally derived lineages of fetal kidney. Although Lgl1 expression is stimulated by glucocorticoids in kidney cells, cortisol (10(-7) M) actually suppresses ureteric bud branching of fetal kidneys from HoxB7/GFP mice in explant culture. However, early branching morphogenesis in the lung and kidney is stimulated by retinoic acid, and we identified putative retinoic acid response elements in the Lgl1 promoter. All-trans-retinoic acid (10(-6) M) stimulated Lgl1 promoter activity and endogenous Lgl1 mRNA expression in vitro. Branching of cultured fetal kidney explants was increased in the presence of all-trans retinoic acid (10(-6) M). Heterozygous Lgl1 knockout mice were crossed to HoxB7/GFP mice to visualize the extent of ureteric bud branching at fetal stages. At embryonic (E) days E12.5-E13.0, mutant Lgl1(+/-) embryos showed a 20% reduction in ureteric bud branching compared with wild-type littermates. We propose a model in which retinoic acid stimulates branching morphogenesis by activating Lgl1 early in development. The prominent effects of glucocorticoids on Lgl1 expression in late lung development suggest a second role for LGL1 in alveolar maturation.

The Novel Lipopolysaccharide-Binding Protein CRISPLD2 Is a Critical Serum Protein to Regulate Endotoxin Function

“…CRISPLD2 is a molecule recognized in the literature, but no LPSrelated functions are attributed to it (21)(22)(23)(24)(25). We were intrigued by the fact that it contains two LCCL domains, which are characteristic LPS-binding structures (26).…”

“…Because it is also known as late gestation lung 1 (Lgl1), it has been implicated in the development of rat lung (21)(22)(23) and mouse kidney (24) and is thought to be involved in the development of nonsyndromic cleft lip with or without cleft palate (25). Its possession of two LCCL domains suggests a relationship to LPS.…”

The CAP Superfamily: Cysteine-Rich Secretory Proteins, Antigen 5, and Pathogenesis-Related 1 Proteins—Roles in Reproduction, Cancer, and Immune Defense

“…Upon return to normal oxygen levels, alveolar regeneration was observed, and Capld2 levels returned to normal, suggesting that Capld2 expression was related to septal growth and alveolar partitioning (127). Similarly, within the E12 mouse kidney corresponding to the initiation of branching, retinoic acid-induced expression of Capld2 was observed with a localization to the mesenchyme surrounding the developing kidney (128). At E13.5, CAPLD2 was observed within the mesenchymal cells in the nephrogenic zone and in stromal cells surrounding the ureteric bud trunk.…”

Induction of Genes Expressed in Endothelial Cells of the Corpus Callosum in the Chronic Cerebral Hypoperfusion Rat Model

“…CRISPLD2/Lgl1 null mice are embryonic lethal by embryonic day 9.5 [60]. CRISPLD2/Lgl1 heterozygous knockout mice appear grossly normal, but lung maturation is delayed and ureteric bud branching is reduced at the fetal stage [60,61]. Chiquet et al [62] reported an association between the CRISPLD2 gene and nonsyndromic cleft lip with or without cleft palate.…”