Double knock-out of Hmga1 and Hipk2 genes causes perinatal death associated to respiratory distress and thyroid abnormalities in mice

Valeria Valente,Raffaele Gerlini,Luigi Di Guida,Giovanna Maria Pierantoni,Gabriella De Vita,Sara Carmela Credendino,Mara Tornincasa,Alfredo Fusco,Francesca Cammarota,Chiara Gentile,Simona Paladino,Andrea Conte,Elena Amendola

doi:10.1038/s41419-019-1975-5

Abstract

The serine–threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) modulates important cellular functions during development, acting as a signal integrator of a wide variety of stress signals, and as a regulator of transcription factors and cofactors. We have previously demonstrated that HIPK2 binds and phosphorylates High-Mobility Group A1 (HMGA1), an architectural chromatinic protein ubiquitously expressed in embryonic tissues, decreasing its binding affinity to DNA. To better define the functional role of HIPK2 and HMGA1 interaction in vivo, we generated mice in which both genes are disrupted. About 50% of these Hmga1/Hipk2 double knock-out (DKO) mice die within 12 h of life (P1) for respiratory failure. The DKO mice present an altered lung morphology, likely owing to a drastic reduction in the expression of surfactant proteins, that are required for lung development. Consistently, we report that both HMGA1 and HIPK2 proteins positively regulate the transcriptional activity of the genes encoding the surfactant proteins. Moreover, these mice display an altered expression of thyroid differentiation markers, reasonably because of a drastic reduction in the expression of the thyroid-specific transcription factors PAX8 and FOXE1, which we demonstrate here to be positively regulated by HMGA1 and HIPK2. Therefore, these data indicate a critical role of HIPK2/HMGA1 cooperation in lung and thyroid development and function, suggesting the potential involvement of their impairment in the pathogenesis of human lung and thyroid diseases.

Highlights

Homeodomain-interacting protein kinase 2 (HIPK2)belongs to a family of nuclear serine–threonine kinases, originally identified as interactors of homeodomainscontaining corepressor proteins[1]
We report that Hmga1/Hipk[2] double knock-out (DKO) mice die within 12 h of life for respiratory failure, likely owing to impaired lung development associated to a drastic reduction in surfactant proteins, whose expression is positively regulated by both HMGA1b are encoded by the same gene (HMGA1) and HIPK2
We verified the lack of Hmga[1] and Hipk[2] expression in the DKO mice at mRNA and protein level by RT-PCR and Western blot, respectively

Summary

Introduction

Belongs to a family of nuclear serine–threonine kinases, originally identified as interactors of homeodomainscontaining corepressor proteins[1]. Several studies have reported the crucial role of HIPK2 in many biological processes from apoptosis to cell proliferation[2,3]. It is actively involved in cytokinesis, transcriptional regulation, signal transduction, and regulation of protein stability The ability of HIPK2 to bind and phosphorylate several chromatin modifiers and transcription factors likely accounts for the wide spectrum of its biological functions. We have previously identified the nuclear non-histone chromatin high-mobility group A1 proteins as HIPK2 interactors and substrates[9]. HMGA1a and HMGA1b are encoded by the same gene (HMGA1) by alternative splicing

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Conclusion