Ulk4 deficiency leads to hypomyelination in mice

Abstract

Brain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. Here we report that Ulk4 acts as a key regulator of myelination. Myelination is reduced by half in the Ulk4 tm1a/tm1a hypomorph brain, whereas expression of axonal marker genes Tubb3, Nefh, Nefl and Nefm remains unaltered. Transcriptome analyses reveal that 8 (Gfap, Mbp, Mobp, Plp1, Slc1a2, Ttr, Cnp, Scd2) of the 10 most significantly altered genes in the Ulk4 tm1a/tm1a brain are myelination-related. Ulk4 is co-expressed in Olig2 1 (pan-oligodendrocyte marker) and CC1 1 (mature myelinated oligodendrocyte marker) cells during postnatal development.Major oligodendrogeneic transcription factors, including Olig2, Olig1, Myrf, Sox10, Sox8, Sox6, Sox17, Nkx2-2, Nkx6-2 and Carhsp1, are significantly downregulated in the mutants. mRNA transcripts enriched in oligodendrocyte progenitor cells (OPCs), the newly formed oligodendrocytes (NFOs) and myelinating oligodendrocytes (MOs), are significantly attenuated. Expression of stage-specific oligodendrocyte factors including Cspg4, Sox17, Nfasc, Enpp6, Sirt2, Cnp, Plp1, Mbp, Ugt8, Mag and Mog are markedly decreased. Indirect effects of axon caliber and neuroinflammation may also contribute to the hypomyelination, as Ulk4 mutants display smaller axons and increased neuroinflammation. This is the first evidence demonstrating that ULK4 is a crucial regulator of myelination, and ULK4 may therefore become a novel therapeutic target for hypomyelination diseases. K E Y W O R D Shypomyelination, knockout mice, oligodendrogenesis, Ulk4, white matter integrity

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

“…55 ULK4 belongs to the family of serinethreonine protein kinases, a group of phosphorylating kinases involved in diverse processes including cell proliferation and differ entiation, apoptosis, and embryonic development. Its deficiency leads to hypomyelination, 56 and it has been associated with neuropsychiatric traits. 57 Finally, we report a novel association on chromosome 18, located between ZBTB14, encoding a zinc finger transcription factor (zinc finger and BTB domaincontaining protein 14), and EPB41L3, encoding for a membrane protein that inhibits cell proliferation and promotes apoptosis (erythrocyte mem brane protein band 4•1like 3).…”

Increased Ca2+ signaling in NRXN1α+/− neurons derived from ASD induced pluripotent stem cells

“…RNASeq was performed by BGI as described previously [54–57] on day 100 cortical neurons from six control iPSC lines of four donors and four NRXN1α +/− lines of three patients. Transcripts were aligned to GRCH37/hg19, and abundance quantified from the FASTQ in Kallisto (v0.43.1) and presented as transcripts per million (TPM).…”

Intragenic Microdeletion of <b><i>ULK4</i></b> and Partial Microduplication of <b><i>BRWD3</i></b> in Siblings with Neuropsychiatric Features and Obesity

“…Ciliary disorders may be isolated or syndromic, and common features are cystic liver and/or kidney disease, blindness, neural tube defects, brain anomalies and intellectual disability, skeletal abnormalities ranging from polydactyly to abnormally short ribs and limbs, ectodermal defects, obesity, situs inversus, infertility, and recurrent respiratory tract infections [Oud et al, 2017]. Liu et al [2017Liu et al [ , 2018b, demonstrated that ULK4 is also a crucial regulator of myelination. Moreover, Liu et al [2018 a ] have shown for the first time that Ulk4 haploinsufficiency in mice leads to increased anxiety-related behavior with disturbed GABAergic signaling.…”