Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient

Satomi Yogosawa,Mitsuru Morimoto,Izuho Hatada,Shinya Toyokuni,Makiko Ohkido,Kiyotsugu Yoshida,Takuro Horii,Yasumasa Okazaki,Saishu Yoshida,Jun Nakayama

doi:10.1038/s42003-021-02734-6

Abstract

Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood. Here we show that Dyrk2-deficient mice display congenital malformations in multiple organs. Transcriptome analysis reveals molecular pathology of Dyrk2-deficient mice, particularly with respect to Foxf1 reduction. Mutant pups exhibit sudden death soon after birth due to respiratory failure. Detailed analyses of primordial lungs at the early developmental stage demonstrate that Dyrk2 deficiency leads to altered airway branching and insufficient alveolar development. Furthermore, the Foxf1 expression gradient in mutant lung mesenchyme is disrupted, reducing Foxf1 target genes, which are necessary for proper airway and alveolar development. In ex vivo lung culture system, we rescue the expression of Foxf1 and its target genes in Dyrk2-deficient lung by restoring Shh signaling activity. Taken together, we demonstrate that Dyrk2 is essential for embryogenesis and its disruption results in congenital malformation.

Highlights

Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood
We have previously shown that Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) exerts anti-tumor effects in various cancer cells[21,22,24,25,29]
Since embryogenesis is a wellorchestrated process that is tightly regulated by transcription factors, we focused on the transcription factor genes (97 probes in E8.5 and 65 probes in E10.5) that may be implicated in the abnormal phenotypes of Dyrk2−/− embryos

Summary

Introduction

Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood. The analysis of molecular pathology of congenital malformations provides a better understanding of the etiology of pediatric diseases, which identify essential genes in normal development. In addition to improving our understanding of the particular genes in development, the genetic knockout of these genes in mice often reproduces congenital malformations, providing extremely insightful information for the study of refractory pediatric diseases[3,4,5,6,7,8]. Genetic studies of mice have previously demonstrated that Foxf[1] transcription in the lung mesenchyme is activated by epithelial Shh via epithelial-to-mesenchymal interaction and is required for airway branching morphogenesis[15,16]. We find that Dyrk2-deficient mice exhibit congenital malformations of multiple organs and death soon after birth due to respiratory failure. We show that kinase activity of epithelial Dyrk[2] is involved in proper lung mesenchymal development by regulating Shh signaling

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Results

Conclusion