haploinsufficiency induces an eye-open-at-birth phenotype in the DBA/2 background.

Autotaxin, encoded by the gene, produces lysophosphatidic acid (LPA), which exerts numerous biological functions via its cognate receptors. null mutant mice die by embryonic day 9.5 owing to aberrant vascular development in the yolk sac, preventing analysis after that period.

The autotaxin-LPA axis promotes membrane trafficking and secretion in yolk sac visceral endoderm cells.

Autotaxin, encoded by the Enpp2 gene, is an exoenzyme that produces lysophosphatidic acid, thereby regulating many biologic functions. We previously reported that Enpp2 mRNA was abundantly expressed in yolk sac visceral endoderm (VE) cells and that Enpp2-/- mice were lethal at embryonic day 9.5 owing to angiogenic defects in the yolk sac.

Feasibility of Support by Family Practitioners in Reducing Colorectal Cancer-Related Death among Outpatients Who Have Not Undergone Colorectal Cancer Screening.

We aimed to clarify the effectiveness of interventions in outpatients who did not undergo colorectal cancer (CRC) screening. From September 2012 to August 2013, we conducted a project, which showed that the immunological fecal occult blood test (FOBT) was actively recommended for outpatients who were ≥40 years of age, attended the Marumori Hospital regularly, and were not screened for CRC in the previous two years. We evaluated the detection rate of CRC and the disease specific survival ratio in February 2021 among patients with positive FOBT results during the retrospective cohort study.

Diffusion magnetic resonance tractography-based evaluation of commissural fiber abnormalities in a heparan sulfate endosulfatase-deficient mouse brain.

During brain development, neural circuits are formed through cellular differentiation, cell migration, axon guidance, and synaptogenic processes by the coordinated actions of many genes. Abnormalities in neural development, especially connectivity defects, can result in psychiatric disorders, such as schizophrenia and autism. Recent advances in diffusion tensor imaging have enabled us to examine the brain's macroscopic nerve trajectories.

Expression of Heparan Sulfate Endosulfatases in the Adult Mouse Brain: Co-expression of and Dopamine D1/D2 Receptors.

The heparan sulfate 6--endosulfatases, Sulfatase 1 (Sulf1), and Sulfatase 2 (Sulf2), are extracellular enzymes that regulate cellular signaling by removing 6--sulfate from the heparan sulfate chain. Although previous studies have revealed that are essential for normal development, their functions in the adult brain remain largely unknown. To gain insight into their neural functions, we used hybridization to systematically examine mRNA expression in the adult mouse brain.

Regulation of fractone heparan sulfate composition in young and aged subventricular zone neurogenic niches.

Fractones, specialized extracellular matrix structures found in the subventricular zone (SVZ) neurogenic niche, can capture growth factors, such as basic fibroblast growth factor, from the extracellular milieu through a heparin-binding mechanism for neural stem cell (NSC) presentation, which promotes neurogenesis. During aging, a decline in neurogenesis correlates with a change in the composition of heparan sulfate (HS) within fractones. In this study, we used antibodies that recognize specific short oligosaccharides with varying sulfation to evaluate the HS composition in fractones in young and aged brains.

Abnormal Pyramidal Decussation and Bilateral Projection of the Corticospinal Tract Axons in Mice Lacking the Heparan Sulfate Endosulfatases, Sulf1 and Sulf2.

The corticospinal tract (CST) plays an important role in controlling voluntary movement. Because the CST has a long trajectory throughout the brain toward the spinal cord, many axon guidance molecules are required to navigate the axons correctly during development. Previously, we found that double-knockout (DKO) mouse embryos lacking the heparan sulfate endosulfatases, and , showed axon guidance defects of the CST owing to the abnormal accumulation of Slit2 protein on the brain surface.

Data for 3D reconstruction of the corticospinal tract in the wild-type and Semaphorin 6A knockout adult brain.

The corticospinal tract (CST) has a complex and long trajectory throughout the brain. Semaphorin 6A (Sema6A), a member of the semaphorin family, is one of the important regulators of CST axon guidance. Previous studies have shown that knockout (KO) mice have CST defects at the midbrain-hindbrain boundary and medulla [1].

Remarkable complexity and variability of corticospinal tract defects in adult Semaphorin 6A knockout mice.

The corticospinal tract (CST) has a complex and long trajectory that originates in the cerebral cortex and ends in the spinal cord. Semaphorin 6A (Sema6A), a member of the semaphorin family, is an important regulator of CST axon guidance. Previous studies have shown that postnatal Sema6A mutant mice have CST defects at the midbrain-hindbrain boundary and medulla.

Desulfation of Heparan Sulfate by Sulf1 and Sulf2 Is Required for Corticospinal Tract Formation.

Heparan sulfate (HS) has been implicated in a wide range of cell signaling. Here we report a novel mechanism in which extracellular removal of 6-O-sulfate groups from HS by the endosulfatases, Sulf1 and Sulf2, is essential for axon guidance during development. In Sulf1/2 double knockout (DKO) mice, the corticospinal tract (CST) was dorsally displaced on the midbrain surface.

Structural basis for Ccd1 auto-inhibition in the Wnt pathway through homomerization of the DIX domain.

Wnt signaling plays an important role in governing cell fate decisions. Coiled-coil-DIX1 (Ccd1), Dishevelled (Dvl), and Axin are signaling proteins that regulate the canonical pathway by controlling the stability of a key signal transducer β-catenin. These proteins contain the DIX domain with a ubiquitin-like fold, which mediates their interaction in the β-catenin destruction complex through dynamic head-to-tail polymerization.

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.

Proteoglycans and axon guidance: a new relationship between old partners.

Neural circuits are formed with great precision during development. Accumulated evidence over the past three decades has demonstrated that growing axons are navigated toward their targets by the combined actions of attractants and repellents together with their receptors. It has long been known that proteoglycans, glycosylated proteins possessing covalently attached glycosaminoglycans, play a critical role in axon guidance; however, the molecular mechanisms by which proteoglycans regulate axon behaviors remain largely unknown.

Heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, regulate glomerular integrity by modulating growth factor signaling.

Glomerular integrity and functions are maintained by growth factor signaling. Heparan sulfate, the major component of glomerular extracellular matrixes, modulates growth factor signaling, but its roles in glomerular homeostasis are unknown. We investigated the roles of heparan sulfate 6-O-endosulfatases, sulfatase (Sulf)1 and Sulf2, in glomerular homeostasis.

Expression of the heparan sulfate 6-O-endosulfatases, Sulf1 and Sulf2, in the avian and mammalian inner ear suggests a role for sulfation during inner ear development.

Background: Inner ear morphogenesis is tightly regulated by the temporally and spatially coordinated action of signaling ligands and their receptors. Ligand-receptor interactions are influenced by heparan sulfate proteoglycans (HSPGs), cell surface molecules that consist of glycosaminoglycan chains bound to a protein core. Diversity in the sulfation pattern within glycosaminoglycan chains creates binding sites for numerous cell signaling factors, whose activities and distribution are modified by their association with HSPGs.

A synthesized nostocionone derivative potentiates programmed cell death in human T-cell leukemia Jurkat cells through mitochondria via the release of endonuclease G.

Nostocionone (Nost), a compound isolated from Nostoc commune, and its synthesized derivatives (NostDs) were evaluated for in vitro cytotoxicity against human T-cell leukemia Jurkat cells. NostD3 [(1E,4E)-1-(3,4-dihydroxyphenyl)-5-(2,6,6-trimethylcyclohex-1-enyl)penta-1,4-dien-3-one] inhibited cell growth more potently than Nost. To elucidate the mechanisms of NostD3-induced cell death, we examined changes in cell morphology, the loss of mitochondrial membrane potential (MMT), and DNA fragmentation.

A unique mouse model for investigating the properties of amyotrophic lateral sclerosis-associated protein TDP-43, by in utero electroporation.

TDP-43 is a discriminative protein that is found as intracellular aggregations in the neurons of the cerebral cortex and spinal cord of patients with amyotrophic lateral sclerosis (ALS); however, the mechanisms of neuron loss and its relation to the aggregations are still unclear. In this study, we generated a useful model to produce TDP-43 aggregations in the motor cortex using in utero electroporation on mouse embryos. The plasmids used were full-length TDP-43 and C-terminal fragments of TDP-43 (wild-type or M337V mutant) tagged with GFP.

ErbB2 dephosphorylation and anti-proliferative effects of neuregulin-1 in ErbB2-overexpressing cells; re-evaluation of their low-affinity interaction.

Neuregulin-1 binds to ErbB3 and ErbB4 and regulates cancer proliferation and differentiation. Neuregulin-1 had been suggested to also react with ErbB2, but this argument becomes controversial. Here, we re-evaluated the cellular responses and ErbB2 interaction of neuregulin-1 in ErbB2 overexpressing cell lines.

Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis.

Rheumatoid arthritis is a destructive arthropathy characterized by chronic synovial inflammation that imposes a substantial socioeconomic burden. Under the influence of the proinflammatory milieu, synovial fibroblasts (SFs), the main effector cells in disease pathogenesis, become activated and hyperplastic, releasing proinflammatory factors and tissue-remodeling enzymes. This study shows that activated arthritic SFs from human patients and animal models express significant quantities of autotaxin (ATX; ENPP2), a lysophospholipase D that catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA).

Organ-specific sulfation patterns of heparan sulfate generated by extracellular sulfatases Sulf1 and Sulf2 in mice.

Heparan sulfate endosulfatases Sulf1 and Sulf2 hydrolyze 6-O-sulfate in heparan sulfate, thereby regulating cellular signaling. Previous studies have revealed that Sulfs act predominantly on UA2S-GlcNS6S disaccharides and weakly on UA-GlcNS6S disaccharides. However, the specificity of Sulfs and their role in sulfation patterning of heparan sulfate in vivo remained unknown.

Impaired vascular remodeling in the yolk sac of embryos deficient in ROCK-I and ROCK-II.

Rho-associated coiled-coil-forming protein serine/threonine kinase (ROCK) consisting of two isoforms, ROCK-I and ROCK-II, functions downstream of the small GTPase Rho for assembly of actomyosin bundles. To examine the role of ROCK isoforms in vivo, we previously generated and examined mice deficient in each of the two isoforms individually. Here, we further examined the in vivo role of ROCK isoforms by generating mice deficient in both isoforms.

Crystallographic characterization of the DIX domain of the Wnt signalling positive regulator Ccd1.

Coiled-coil DIX1 (Ccd1) is a positive regulator that activates the canonical Wnt signalling pathway by inhibiting the degradation of the key signal transducer β-catenin. The C-terminal DIX domain of Ccd1 plays an important role in the regulation of signal transduction through homo-oligomerization and protein complex formation with other DIX domain-containing proteins, i.e.

Autotaxin is required for the cranial neural tube closure and establishment of the midbrain-hindbrain boundary during mouse development.

Autotaxin (ATX) is a lysophospholipid-generating exoenzyme expressed in embryonic and adult neural tissues. We previously showed that ATX is expressed in the neural organizing centers, anterior head process, and midbrain-hindbrain boundary (MHB). To elucidate the role of ATX during neural development, here we examined the neural phenotypes of ATX-deficient mice.

Deficiency of autotaxin/lysophospholipase D results in head cavity formation in mouse embryos through the LPA receptor-Rho-ROCK pathway.

Autotaxin, encoded by the Enpp2 gene, generates lysophosphatidic acid (LPA) extracellularly, eliciting various cellular responses through specific LPA receptors. Previous studies have revealed that Enpp2(-/-) mice die at E9.5 owing to angiogenic defects in the yolk sac.