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Multiple roles of Ulk4 in neurogenesis and brain function.

ABSTRACT: Neurogenesis is essential for proper brain formation and function, and abnormal neural proliferation is an underlying neuropathology of many brain disorders. Recent advances on adult neurogenesis demonstrate that neural stem cells (NSCs) at the subventricular zone (SVZ) are largely derived during mid-embryonic neurogenesis from a subset of cells, which slow down in their pace of cell division,1 become quiescent cells and can be reactivated in need.2 The NSCs at birth constitute the stem cell pool for both postnatal oligodendrogenesis3 and adult neurogenesis.1,2 However, little is known about factors that control the size of NSC pool. The article published in Stem Cells on Jun 14, 2016 by Liu and colleagues described a member of the Unc-51-like serine/threonine kinase family, Ulk4, which plays a critical role in regulating the NSC pool size.4 Authors presented evidence of cell cycle-dependent Ulk4 expression in vitro and in vivo, and reduced NSC pool in targetedly disrupted Ulk4 newborn mice, with disturbed pathways of cell cycle regulation and WNT signaling (Fig. 1), suggesting that ULK4 may be associated with neurodevelopmental, neuropsychiatric as well as neurodegenerative diseases.

SUBMITTER: Liu M

PROVIDER: S-EPMC5449176 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Multiple roles of Ulk4 in neurogenesis and brain function.

Liu Min M Xu Ping P O'Brien Timothy T Shen Sanbing S

Neurogenesis (Austin, Tex.) 20170523 1

Neurogenesis is essential for proper brain formation and function, and abnormal neural proliferation is an underlying neuropathology of many brain disorders. Recent advances on adult neurogenesis demonstrate that neural stem cells (NSCs) at the subventricular zone (SVZ) are largely derived during mid-embryonic neurogenesis from a subset of cells, which slow down in their pace of cell division,<sup>1</sup> become quiescent cells and can be reactivated in need.<sup>2</sup> The NSCs at birth consti ...[more]

PMID: 28596978

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Project description: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.

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Multiple roles of Ulk4 in neurogenesis and brain function.

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Multiple roles of Ulk4 in neurogenesis and brain function.

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