Functional analysis of pathogenic variants in LAMB1-related leukoencephalopathy reveals genotype-phenotype correlations and suggests its role in glial cells.

Laminin B1 (LAMB1) is one of the extracellular matrix (ECM) proteins that make up the basement membrane. Early frameshift, late frameshift, and missense variants in LAMB1 have been reported to cause rare monogenic neurological disorders that are collectively known as LAMB1-related leukoencephalopathy. Although there is some genotype-phenotype correlation, functional consequences of pathogenic LAMB1 variants are largely unknown.

Pathogenic missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes.

-associated syndrome (SAS) is caused by pathogenic variants in , which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with variants that affect p.

PAK1 Positively Regulates Oligodendrocyte Morphology and Myelination.

The actin cytoskeleton is crucial for oligodendrocyte differentiation and myelination. Here we show that p21-activated kinase 1 (PAK1), a well-known actin regulator, promotes oligodendrocyte morphologic change and myelin production in the CNS. A combination of and models demonstrated that PAK1 is expressed throughout the oligodendrocyte lineage with highest expression in differentiated oligodendrocytes.

Mechanistic Target of Rapamycin Regulates the Oligodendrocyte Cytoskeleton during Myelination.

During differentiation, oligodendrocyte precursor cells (OPCs) extend a network of processes that make contact with axons and initiate myelination. Recent studies revealed that actin polymerization is required for initiation of myelination whereas actin depolymerization promotes myelin wrapping. Here, we used primary OPCs in culture isolated from neonatal rat cortices of both sexes and young male and female mice with oligodendrocyte-specific deletion of mechanistic target of rapamycin (mTOR) to demonstrate that mTOR regulates expression of specific cytoskeletal targets and actin reorganization in oligodendrocytes during developmental myelination.

The mechanistic target of rapamycin pathway downregulates bone morphogenetic protein signaling to promote oligodendrocyte differentiation.

Oligodendrocyte precursor cells (OPCs) differentiate and mature into oligodendrocytes, which produce myelin in the central nervous system. Prior studies have shown that the mechanistic target of rapamycin (mTOR) is necessary for proper myelination of the mouse spinal cord and that bone morphogenetic protein (BMP) signaling inhibits oligodendrocyte differentiation, in part by promoting expression of inhibitor of DNA binding 2 (Id2). Here we provide evidence that mTOR functions specifically in the transition from early stage OPC to immature oligodendrocyte by downregulating BMP signaling during postnatal spinal cord development.

Strong sonic hedgehog signaling in the mouse ventral spinal cord is not required for oligodendrocyte precursor cell (OPC) generation but is necessary for correct timing of its generation.

In the mouse neural tube, sonic hedgehog (Shh) secreted from the floor plate (FP) and the notochord (NC) regulates ventral patterning of the neural tube, and later is essential for the generation of oligodendrocyte precursor cells (OPCs). During early development, the NC is adjacent to the neural tube and induces ventral domains in it, including the FP. In the later stage of development, during gliogenesis in the spinal cord, the pMN domain receives strong Shh signaling input.

Photochemical Acceleration of DNA Strand Displacement by Using Ultrafast DNA Photo-crosslinking.

DNA strand displacement is an essential reaction in genetic recombination, biological processes, and DNA nanotechnology. In particular, various DNA nanodevices enable complicated calculations. However, it takes time before the output is obtained, so acceleration of DNA strand displacement is required for a rapid-response DNA nanodevice.

Sulfatase 2 Modulates Fate Change from Motor Neurons to Oligodendrocyte Precursor Cells through Coordinated Regulation of Shh Signaling with Sulfatase 1.

Sulfatases (Sulfs) are a group of endosulfatases consisting of Sulf1 and Sulf2, which specifically remove sulfate from heparan sulfate proteoglycans. Although several studies have shown that Sulf1 acts as a regulator of sonic hedgehog (Shh) signaling during embryonic ventral spinal cord development, the detailed expression pattern and function of Sulf2 in the spinal cord remains to be determined. In this study, we found that Sulf2 also modulates the cell fate change from motor neurons (MNs) to oligodendrocyte precursor cells (OPCs) by regulating Shh signaling in the mouse ventral spinal cord in coordination with Sulf1.

Keratan Sulfate Regulates the Switch from Motor Neuron to Oligodendrocyte Generation During Development of the Mouse Spinal Cord.

Keratan sulfate (KS) is a sulfated glycosaminoglycan and has been shown to bind to sonic hedgehog (Shh), which act as a morphogen to regulate the embryonic spinal cord development. We found highly sulfated KS was present in the floor plate (including lateral floor plate) and the notochord . This expression colocalized with Shh expression.

α1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-β/activin-mediated signaling.

It is well known that α1,6-fucosyltransferase (Fut8) and its products, α1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that Fut8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that α1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of α1,6-fucosylation.

Wnt/beta-catenin signaling down-regulates N-acetylglucosaminyltransferase III expression: the implications of two mutually exclusive pathways for regulation.

In previous studies, we reported that N-acetylglucosaminyltransferase III (GnT-III) activity and the enzyme product, bisected N-glycans, both were induced in cells cultured under dense conditions in an E-cadherin-dependent manner (Iijima, J., Zhao, Y., Isaji, T.