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

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology.

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

“…• Repress MEF2-dependent gene expression in undifferentiated myoblasts [231] • Sonic hedgehog-induced proliferation of the mesoderm and neural tube [249] • Eye, ocellar, and bristle development from the neuroectoderm [256] • Maintenance and survival of sensory, sympathetic and dopamine neurons, and glial cell development [248,[250][251][252][253][254] • HIPK4 levels regulate sperm motility, morphology and oocyte binding capacity [233] the active zone, Srpk79d phosphorylates the presynaptic active zone protein Bruchpilot on at least seven arginine-rich N-terminal motifs [175], and knockout of Srpk79d leads to accumulation of Bruchpilot agglomerates, loss of controlled Bruchpilot axonal transport, and aberrant active zone growth and development of synaptic connections. This culminates in failure to maintain nervous system integrity, with locomotor defects and reduced lifespan.…”

“…Hipk3 regulates insulin secretion and glucose tolerance; Hipk4 is required for fertility [83,161,170,232,233,239,[247][248][249][250][251][252][253][254]256,280,341] cell lines [181]. This is then thought to disrupt self-aggregating CAST1/ERC2 complexes that are otherwise required for correct organisation of the presynaptic active zone and subsequent neurotransmitter release [181].…”

“… Sonic hedgehog‐induced proliferation of the mesoderm and neural tube [ 249 ] Eye, ocellar, and bristle development from the neuroectoderm [ 256 ] Maintenance and survival of sensory, sympathetic and dopamine neurons, and glial cell development [ 248 , 250 , 251 , 252 , 253 , 254 ] …”

“…Maintenance and survival of sensory, sympathetic and dopamine neurons, and glial cell development [ 248 , 250 , 251 , 252 , 253 , 254 ]…”

“…[ 83 , 161 , 170 , 232 , 233 , 239 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 256 , 280 , 341 ]…”