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

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.

Phenotypic Effects of Homeodomain-Interacting Protein Kinase 2 Deletion in Mice

“…Therefore, we decided to perform a post-mortem examination of 4-, 12-, and 18-month-old mice. Histological analyses of serial sections from organs and tissues confirmed that their structure and development is overall normal as previously reported [ 22 , 25 ]. However, the brain and spinal cord of Hipk2 -KO mice showed mild to moderate changes, such as scattered neuronal loss in the Purkinje layer of the cerebellum (CBR; Figure 1 D) and in cornu ammonis of hippocampus (CA; Figure 1 E).…”

“…For this reason, the ablation or mutation of one of these targets may contribute to causing a stronger phenotype. For example, we recently found that, when associated with the KO of its target Hmga1 , the loss of Hipk2 causes a lung and thyroid phenotype in the double KO mice, which is completely absent in the single KOs [ 25 ].…”

“…On the other hand, HIPK2 expression strongly increases after skeletal muscle contusion in neutrophils, macrophages, and myofibroblasts [ 24 ]. Finally, we recently reported that the double KO of HIPK2 and high-mobility group A1 (HMGA1), a chromatin non-histone protein previously identified as HIPK2 interactor and substrate, causes perinatal death due to respiratory failure, associated with impaired lung development and reduction in surfactant proteins, as well as reduced expression of thyroid differentiation markers [ 25 ].…”

HMGA Genes and Proteins in Development and Evolution

“…HIPK2 is able to phosphorylate HMGA1, thus decreasing its binding affinity to DNA and altering the HMGA1-mediated regulation of transcriptional activity [258]. The Hmga1/Hipk2 double knock-out mice show an altered lung morphology, possibly caused by the diminished production of surfactant proteins (SP-A, SP-B, and SP-C) necessary for correct lung development [259]. Consistently, HMGA1 and HIPK2 proteins were known to positively regulate the expression of surfactant proteins.…”

“…About 50% of the Hmga1/Hipk2 double knock-out mice die for respiratory failure. In addition, these mice display an altered thyroid differentiation, most probably due to a strong reduction in the expression of the thyroid specific transcription factors PAX8 and FOXE1 [259].…”