ABSTRACT
UNLABELLED: Ciliopathies are an emerging class of devastating disorders with pleiotropic symptoms affecting both the central and peripheral systems and commonly associated with hydrocephalus. Even though ciliary components and three master transcriptional regulators have been identified, little is known about the signaling molecules involved. We previously identified a novel gene, Unc51-like-kinase 4 (ULK4), as a risk factor of neurodevelopmental disorders. Here we took multidisciplinary approaches and uncovered essential roles of Ulk4 in ciliogenesis. We show that Ulk4 is predominantly expressed in the ventricular system, and Ulk4(tm1a/tm1a) ependymal cells display reduced/disorganized cilia with abnormal axonemes. Ulk4(tm1a/tm1a) mice exhibit dysfunctional subcommissural organs, obstructive aqueducts, and impaired CSF flow. Mechanistically, we performed whole-genome RNA sequencing and discovered that Ulk4 regulates the Foxj1 pathway specifically and an array of other ciliogenesis molecules. This is the first evidence demonstrating that ULK4 plays a vital role in ciliogenesis and that deficiency of ULK4 can cause hydrocephalus and ciliopathy-related disorders. SIGNIFICANCE STATEMENT: Ciliopathies are an emerging class of devastating disorders with pleiotropic symptoms affecting both the central and peripheral systems. Ciliopathies are commonly associated with hydrocephalus, and Unc51-like-kinase 4 (Ulk4) has been identified as one of 12 genes causing hydrocephalus in mutants. Here we uncover an essential role of Ulk4 in ciliogenesis. Ulk4 is predominantly expressed in the ventricles, and mutant ependymal cells display reduced/disorganized/nonfunctional motile cilia with abnormal axonemes and impaired CSF flow. Ulk4 modulates expression of the master regulator of ciliogenesis, Foxj1, and other ciliogenesis molecules. This is the first report demonstrating a vital role of Ulk4 in ciliogenesis. ULK4 deficiency may be implicated in human hydrocephalus and other ciliopathy-related disorders.
