An essential role of intestinal cell kinase in lung development is linked to the perinatal lethality of human ECO syndrome

Abstract

Human endocrine-cerebro-osteodysplasia (ECO) syndrome, caused by the loss-of-function mutation R272Q in the ICK (intestinal cell kinase) gene, is a neonatal-lethal developmental disorder. To elucidate the molecular basis of ECO syndrome, we constructed an Ick R272Q knock-in mouse model that recapitulates ECO pathological phenotypes. Newborns bearing Ick R272Q homozygous mutations die at birth due to respiratory distress. Ick mutant lungs exhibit not only impaired branching morphogenesis associated with reduced mesenchymal proliferation, but also significant airspace deficiency in primitive alveoli concomitant with abnormal interstitial mesenchymal differentiation. ICK dysfunction induces elongated primary cilia and perturbs ciliary Hedgehog signaling and autophagy during lung sacculation. Our study identifies an essential role for ICK in lung development and advances the mechanistic understanding of ECO syndrome.

Ciliogenesis associated kinase 1: targets and functions in various organ systems

“…Autopsy revealed obvious lung hypoplasia, among other ECO clinical features. R272Q homozygous lungs had the normal shape, number and arrangement of lobes but were hypoplastic and severely deficient in airspace [23]. These observations support the idea that CILK1 is required for cell proliferation and tissue development in vivo (Table 1).…”

“…During alveolar development at the saccular stage (E16.5–18.5), two major morphogenetic events occur and are required for the formation of air saccules: differentiation of the two main specialized epithelial cell types of the future alveolus, and the thinning and remodeling of lung interstitium. In the developing lung, CILK1 deficiency did not alter the morphology and functions of alveolar type 1 and type 2 epithelial cells but caused hypercellularity in the interstitium . These results suggest that CILK1 function is dispensable for differentiation of alveolar epithelial cells but is essential for the thinning and remodeling of interstitial mesenchyme.…”

“…The bronchial tree develops through extensive proliferation of distal epithelium and surrounding mesenchyme. In CILK1 mutant lungs, reduced proliferation of mesenchymal but not epithelial cells impaired lung branching .…”

“…Later, a knockdown study in human colon cancer cells showed that suppression of CILK1 reduced cell proliferation and G1 cell cycle progression [20]. The essential role of CILK1 in development was further substantiated by both Cilk1 knock-out (KO) [21,22] and Cilk1 mutation knock-in (KI) mouse models [23,24]. Mechanistic analysis of phenotypes in CILK1-deficient mouse models revealed a role for CILK1 in the primary cilium, as described below.…”

“…Surprisingly, epilepsy phenotype can be induced in heterozygous KO mice whose brain structures and neural cilia morphology appear to be indistinguishable from that of wild‐type mice . If one functional allele can produce enough active CILK1 protein to fulfill its role in the formation and maintenance of primary cilia, as suggested by both Cilk1 KO and Cilk1 R272Q KI mouse models , the epilepsy phenotype of CILK1 variants is unlikely the direct consequence of neural ciliary defects. However, since CILK1 is pleiotropic in epilepsy , the genetic background of mouse models may play a critical role in determining the epilepsy phenotype of variants, which should be taken into consideration when designing further studies to elucidate the mechanism underlying the epileptic effect of CILK1 variants.…”