ORCID Profile
0000-0002-5212-254X
Current Organisations
Cincinnati Children's Hospital Medical Center
,
University of Cincinnati Medical Center
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Publications
Crim1 regulates integrin signaling in murine lens development
Publisher: The Company of Biologists
Date: 2015
DOI: 10.1242/DEV.125591
Abstract: The developing lens constitutes a powerful system for investigating the molecular basis of inductive tissue interactions and for studying cataract, the leading cause of blindness. The formation of tightly controlled cell-cell adhesions and cell-matrix junctions between lens epithelial (LE) cells, between lens fiber (LF) cells, and between these two cell populations enables the vertebrate lens to adopt its highly ordered structure and to acquire its optical transparency. Adhesion molecules are thought to maintain this ordered structure, but little is known about their identity or molecular interactions. Cysteine-rich motor neuron 1 (CRIM1), a type I transmembrane protein, is strongly expressed in the developing lens and its mutation causes ocular disease in both mice and humans. However, how Crim1 regulates lens morphogenesis is not understood. We identified a novel ENU-induced hypomorphic allele of Crim1, Crim1glcr11, which in the homozygous state causes cataract and microphthalmia. Using this allele and two other Crim1 mutant alleles, Crim1null and Crim1cko, we show that the lens defects in Crim1 mutants originate from defective LE cell polarity, proliferation and cell adhesion. The Crim1 adhesive function is likely required for interactions both between LE cells and between LE and LF cells. We further show that Crim1 acts in LE cells where it co-localizes with and regulates the levels of active β1 integrin and of phosphorylated FAK and ERK (pFAK, pERK). Lastly, the RGD and transmembrane motifs of Crim1 are required for the regulation of pFAK. These results identify an important function for Crim1 in the regulation of integrin- and FAK-mediated LE cell adhesion during lens development.
Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation
Publisher: The Company of Biologists
Date: 15-11-2010
DOI: 10.1242/DEV.050021
Abstract: Macrophages have been suggested to stimulate neo-lymphangiogenesis in settings of inflammation via two potential mechanisms: (1) acting as a source of lymphatic endothelial progenitor cells via the ability to transdifferentiate into lymphatic endothelial cells and be incorporated into growing lymphatic vessels and (2) providing a crucial source of pro-lymphangiogenic growth factors and proteases. We set out to establish whether cells of the myeloid lineage are important for development of the lymphatic vasculature through either of these mechanisms. Here, we provide lineage tracing evidence to demonstrate that lymphatic endothelial cells arise independently of the myeloid lineage during both embryogenesis and tumour-stimulated lymphangiogenesis in the mouse, thus excluding macrophages as a source of lymphatic endothelial progenitor cells in these settings. In addition, we demonstrate that the dermal lymphatic vasculature of PU.1–/– and Csf1r–/– macrophage-deficient mouse embryos is hyperplastic owing to elevated lymphatic endothelial cell proliferation, suggesting that cells of the myeloid lineage provide signals that act to restrain lymphatic vessel calibre in the skin during development. In contrast to what has been demonstrated in settings of inflammation, macrophages do not comprise the principal source of pro-lymphangiogenic growth factors, including VEGFC and VEGFD, in the embryonic dermal microenvironment, illustrating that the sources of patterning and proliferative signals driving embryonic and disease-stimulated lymphangiogenesis are likely to be distinct.
Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation (Development 137, (3899-3910))
Publisher: The Company of Biologists
Date: 15-02-2011
DOI: 10.1242/DEV.064022
Distinct Functions for Wnt/β-Catenin in Hair Follicle Stem Cell Proliferation and Survival and Interfollicular Epidermal Homeostasis
Publisher: Elsevier BV
Date: 12-2013
Phenotypic and functional characterization of Bst+/- mouse retina
Publisher: The Company of Biologists
Date: 2015
DOI: 10.1242/DMM.018176
Abstract: The belly spot and tail (Bst+/-) mouse phenotype is caused by mutations of the ribosomal protein L24 (Rpl24). Among various phenotypes in Bst+/- mice, the most interesting are its retinal abnormalities, consisting of delayed closure of choroid fissures, decreased ganglion cells, and subretinal vascularization. We further characterized the Bst+/- mice and investigated the underlying molecular mechanisms to assess the feasibility of using this strain as a model for stem cell therapy of retinal degenerative diseases due to retinal ganglion cell (RGC) loss. We found that, although RGC are significantly reduced in retinal ganglion cell layer in Bst+/- mouse, melanopsin-positive RGC, also called ipRGCs, appear to be unchanged. Pupillary light reflex (PLR) was completely absent in Bst+/- mice, but they had a normal circadian rhythm. In order to examine the pathological abnormalities in Bst+/- mice, we performed electronic microscopy (EM) in RGC and found that mitochondria morphology was deformed, having irregular borders and lacking cristae. The complex activities of mitochondrial electron transport chain were decreased significantly. Finally, for subretinal vascularization, we also found that angiogenesis is delayed in Bst+/- associated with delayed haloid regression. Characterization of Bst+/- retina suggests that the Bst+/- mouse strain could be a useful murine model, which can be used to further explore the pathogenesis and strategy of treatment of retinal degenerative diseases through employing stem cell technology.
Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury
Publisher: Springer Science and Business Media LLC
Date: 15-10-2015
Related Organisations
New York University Skirball Institute Of Biomolecular Medicine
Location: United States of America
Cincinnati Children's Hospital Medical Center
Location: United States of America
University Of Cincinnati Medical Center
Location: United States of America
Related Funding Activities
No related grants have been discovered for Richard Lang.