scholarly journals A mouse model for kinesin family member 11 (Kif11)-associated familial exudative vitreoretinopathy

2020 ◽  
Vol 29 (7) ◽  
pp. 1121-1131
Author(s):  
Yanshu Wang ◽  
Philip M Smallwood ◽  
John Williams ◽  
Jeremy Nathans
Keyword(s):  
Vascular Endothelial Cells ◽  
Postnatal Growth ◽  
Conditional Knockout ◽  
Beta Catenin ◽  
Vascular Endothelial ◽  
Stunted Growth ◽  
Human Disorders ◽  
Principal Finding ◽  
The Central Nervous System ◽  
Spindle Function

Abstract During mitosis, Kif11, a kinesin motor protein, promotes bipolar spindle formation and chromosome movement, and during interphase, Kif11 mediates diverse trafficking processes in the cytoplasm. In humans, inactivating mutations in KIF11 are associated with (1) retinal hypovascularization with or without microcephaly and (2) multi-organ syndromes characterized by variable combinations of lymphedema, chorioretinal dysplasia, microcephaly and/or mental retardation. To explore the pathogenic basis of KIF11-associated retinal vascular disease, we generated a Kif11 conditional knockout (CKO) mouse and investigated the consequences of early postnatal inactivation of Kif11 in vascular endothelial cells (ECs). The principal finding is that postnatal EC-specific loss of Kif11 leads to severely stunted growth of the retinal vasculature, mildly stunted growth of the cerebellar vasculature and little or no effect on the vasculature elsewhere in the central nervous system (CNS). Thus, in mice, Kif11 function in early postnatal CNS ECs is most significant in the two CNS regions—the retina and cerebellum—that exhibit the most rapid rate of postnatal growth, which may sensitize ECs to impaired mitotic spindle function. Several lines of evidence indicate that these phenotypes are not caused by reduced beta-catenin signaling in ECs, despite the close resemblance of the Kif11 CKO phenotype to that caused by EC-specific reductions in beta-catenin signaling. Based on prior work, defective beta-catenin signaling had been the only known mechanism responsible for monogenic human disorders of retinal hypovascularization. The present study implies that retinal hypovascularization can arise from a second and mechanistically distinct cause.

scholarly journals Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mark F Sabbagh ◽  
Jacob S Heng ◽  
Chongyuan Luo ◽  
Rosa G Castanon ◽  
Joseph R Nery ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial Cell ◽  
Regulatory Elements ◽  
Vascular Endothelial ◽  
Organ Specific ◽  
The Central Nervous System ◽  
Tf Gene ◽  
Canonical Wnt ◽  
Tip Cells

Vascular endothelial cell (EC) function depends on appropriate organ-specific molecular and cellular specializations. To explore genomic mechanisms that control this specialization, we have analyzed and compared the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) gene expression and TF motifs at candidate cis-regulatory elements reveals both shared and organ-specific EC regulatory networks. In the embryo, only those ECs that are adjacent to or within the central nervous system (CNS) exhibit canonical Wnt signaling, which correlates precisely with blood-brain barrier (BBB) differentiation and Zic3 expression. In the early postnatal brain, single-cell RNA-seq of purified ECs reveals (1) close relationships between veins and mitotic cells and between arteries and tip cells, (2) a division of capillary ECs into vein-like and artery-like classes, and (3) new endothelial subtype markers, including new validated tip cell markers.

scholarly journals High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Szandor Simmons ◽  
Naoko Sasaki ◽  
Eiji Umemoto ◽  
Yutaka Uchida ◽  
Shigetomo Fukuhara ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Conditional Knockout ◽  
Vascular Endothelial ◽  
High Endothelial Venules ◽  
Vascular Integrity ◽  
Autocrine Control ◽  
Sphingosine 1 Phosphate ◽  
Lymphocyte Egress

While the sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor-1 (S1PR1) axis is critically important for lymphocyte egress from lymphoid organs, S1PR1-activation also occurs in vascular endothelial cells (ECs), including those of the high-endothelial venules (HEVs) that mediate lymphocyte immigration into lymph nodes (LNs). To understand the functional significance of the S1P/S1PR1-Gi axis in HEVs, we generated Lyve1;Spns2Δ/Δ conditional knockout mice for the S1P-transporter Spinster-homologue-2 (SPNS2), as HEVs express LYVE1 during development. In these mice HEVs appeared apoptotic and were severely impaired in function, morphology and size; leading to markedly hypotrophic peripheral LNs. Dendritic cells (DCs) were unable to interact with HEVs, which was also observed in Cdh5CRE-ERT2;S1pr1Δ/Δ mice and wildtype mice treated with S1PR1-antagonists. Wildtype HEVs treated with S1PR1-antagonists in vitro and Lyve1-deficient HEVs show severely reduced release of the DC-chemoattractant CCL21 in vivo. Together, our results reveal that EC-derived S1P warrants HEV-integrity through autocrine control of S1PR1-Gi signaling, and facilitates concomitant HEV-DC interactions.

scholarly journals Intracranial capillary hemangioma mimicking a dissociative disorder

2012 ◽  
Vol 2 (2) ◽  
pp. 35 ◽  
Author(s):  
Santosh G. John ◽  
Unnikrishnan Pillai ◽  
Alexander Lacasse
Keyword(s):  
Complete Resolution ◽  
Vascular Endothelial Cells ◽  
Capillary Hemangioma ◽  
Neurological Deficits ◽  
Dissociative Disorder ◽  
Vascular Endothelial ◽  
Total Excision ◽  
Syndrome Patient ◽  
Behavioral Abnormalities ◽  
The Central Nervous System

Capillary hemangiomas, hamartomatous proliferation of vascular endothelial cells, are rare in the central nervous system (CNS). Intracranial capillary hemangiomas presenting with reversible behavioral abnormalities and focal neurological deficits have rarely been reported. We report a case of CNS capillary hemangioma presenting with transient focal neurological deficits and behavioral abnormalities mimicking Ganser’s syndrome. Patient underwent total excision of the vascular malformation, resulting in complete resolution of his symptoms.

Interactions and fates of avian craniofacial mesenchyme

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 121-140 ◽  
Author(s):  
Drew M. Noden
Keyword(s):  
Connective Tissue ◽  
Neural Crest ◽  
Spatial Information ◽  
Vascular Endothelial Cells ◽  
Paraxial Mesoderm ◽  
Avian Embryo ◽  
Vascular Endothelial ◽  
Connective Tissues ◽  
The Central Nervous System ◽  
Lateral Mesoderm

Craniofacial mesenchyme is composed of three mesodermal populations – prechordal plate, lateral mesoderm and paraxial mesoderm, which includes the segmented occipital somites and the incompletely segmented somitomeres – and the neural crest. This paper outlines the fates of each of these, as determined using quail–chick chimaeras, and presents similarities and differences between these cephalic populations and their counterparts in the trunk. Prechordal and paraxial mesodermal populations are the sources of all voluntary muscles of the head. The latter also provides most of the connective precursors of the calvaria, occipital, otic–parietal and basisphenoid tissues. Lateral mesoderm is the source of peripharyngeal connective tissues; the most rostral skeletal tissues it forms are the laryngeal and tracheal cartilages. When migrating neural crest cells encounter segmented paraxial mesoderm (occipital and trunk somites), most move into the region between the dermamyotome and sclerotome in the cranial half of each somite. In contrast, most cephalic crest cells migrate superficial to somitomeres. There is, however, a small subpopulation of the head crest that invades somitomeric mesoderm. These cells subsequently segregate presumptive myogenic precursors of visceral arch voluntary muscles from underlying mesenchyme. In the neurula-stage avian embryo, all paraxial and lateral mesodermal populations contain precursors of vascular endothelial cells, which can be detected in chimaeric embryos using anti-quail endothelial antibodies. Some of these angioblasts differentiate in situ, contributing directly to pre-existing vessels or forming isolated, nonpatent, cords that subsequently vesiculate and fuse with nearby vessels. Many angioblasts migrate in all directions, invading embryonic mesenchymal and epithelial tissues and participating in new blood vessel formation in distant sites. The interactions leading to proper spatial patterning of craniofacial skeletal, muscular, vascular and peripheral neural tissues has been studied by performing heterotopic transplants of each of these mesodermal and neural crest populations. The results consistently indicate that connective tissue precursors, regardless of their origin, contain spatial information used by the precursors of muscles and blood vessels and by outgrowing peripheral nerves. Some of these connective tissue precursors (e.g. the neural crest, paraxial mesoderm) acquire their spatial programming while in association with the central nervous system or developing sensory epithelia (e.g. otic, optic, nasal epithelia).

scholarly journals Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine

2019 ◽  
Vol 32 (5) ◽  
pp. 307-319 ◽  
Author(s):  
Yuanbo Zhu ◽  
Guangwei Cui ◽  
Eiji Miyauchi ◽  
Yuki Nakanishi ◽  
Hisa Mukohira ◽  
...  
Keyword(s):  
Vascular Endothelial Cells ◽  
Hematopoietic Cells ◽  
Cell Number ◽  
Conditional Knockout ◽  
Vascular Endothelial ◽  
Intestinal Epithelial ◽  
Functional Maturation ◽  
Interleukin 15 ◽  
Precise Role

Abstract Abstract Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.

VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions

1998 ◽  
Vol 111 (20) ◽  
pp. 3045-3057 ◽  
Author(s):  
A.P. Kowalczyk ◽  
P. Navarro ◽  
E. Dejana ◽  
E.A. Bornslaeger ◽  
K.J. Green ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Epithelial Cells ◽  
Intermediate Filament ◽  
Vascular Endothelial Cells ◽  
Intercellular Junctions ◽  
Microvascular Endothelial Cells ◽  
Beta Catenin ◽  
Vascular Endothelial ◽  
Microvascular Endothelial ◽  
Cell Cell

Vascular endothelial cells assemble adhesive intercellular junctions comprising a unique cadherin, VE-cadherin, which is coupled to the actin cytoskeleton through cytoplasmic interactions with plakoglobin, beta-catenin and alpha -catenin. However, the potential linkage between VE-cadherin and the vimentin intermediate filament cytoskeleton is not well characterized. Recent evidence indicates that lymphatic and vascular endothelial cells express desmoplakin, a cytoplasmic desmosomal protein that attaches intermediate filaments to the plasma membrane in epithelial cells. In the present study, desmoplakin was localized to intercellular junctions in human dermal microvascular endothelial cells. To determine if VE-cadherin could associate with desmoplakin, VE-cadherin, plakoglobin, and a desmoplakin amino-terminal polypeptide (DP-NTP) were co-expressed in L-cell fibroblasts. In the presence of VE-cadherin, both plakoglobin and DP-NTP were recruited to cell-cell borders. Interestingly, beta-catenin could not substitute for plakoglobin in the recruitment of DP-NTP to cell borders, and DP-NTP bound to plakoglobin but not beta-catenin in the yeast two-hybrid system. In addition, DP-NTP colocalized at cell-cell borders with alpha-catenin in the L-cell lines, and endogenous desmoplakin and alpha-catenin colocalized in cultured dermal microvascular endothelial cells. This is in striking contrast to epithelial cells, where desmoplakin and alpha -+catenin are restricted to desmosomes and adherens junctions, respectively. These results suggest that endothelial cells assemble unique junctional complexes that couple VE-cadherin to both the actin and intermediate filament cytoskeleton.

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