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University Administration and Governance

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This community includes Virginia Tech administrative offices and governance units.

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Browsing University Administration and Governance by Department "Fralin Biomedical Research Institute"

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    Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development
    Ates, Kristin M.; Wang, Tong; Moreland, Trevor; Veeranan-Karmegam, Rajalakshmi; Ma, Manxiu; Jeter, Chelsi; Anand, Priya; Wenzel, Wolfgang; Kim, Hyung-Goo; Wolfe, Lynne A.; Stephen, Joshi; Adams, David R.; Markello, Thomas; Tifft, Cynthia J.; Settlage, Robert E.; Gahl, William A.; Gonsalvez, Graydon B.; Malicdan, May Christine; Flanagan-Steet, Heather; Pan, Yuchin Albert (2020-05)
    A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, phetal and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.
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    Specific labeling of synaptic schwann cells reveals unique cellular and molecular features
    Castro, Ryan W.; Taetzsch, Thomas; Vaughan, Sydney K.; Godbe, Kerilyn; Chappell, John C.; Settlage, Robert E.; Valdez, Gregorio (2020-06-25)
    Perisynaptic Schwann cells (PSCs) are specialized, non-myelinating, synaptic glia of the neuromuscular junction (NMJ), that participate in synapse development, function, maintenance, and repair. The study of PSCs has relied on an anatomy-based approach, as the identities of cell-specific PSC molecular markers have remained elusive. This limited approach has precluded our ability to isolate and genetically manipulate PSCs in a cell specific manner. We have identified neuron-glia antigen 2 (NG2) as a unique molecular marker of S100 beta+ PSCs in skeletal muscle. NG2 is expressed in Schwann cells already associated with the NMJ, indicating that it is a marker of differentiated PSCs. Using a newly generated transgenic mouse in which PSCs are specifically labeled, we show that PSCs have a unique molecular signature that includes genes known to play critical roles in PSCs and synapses. These findings will serve as a springboard for revealing drivers of PSC differentiation and function.