ORCID Profile
0000-0002-3665-3738
Current Organisations
Hospital for Sick Children
,
University of Maryland Baltimore County Biological Sciences
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Oxford University Press (OUP)
Date: 16-06-2012
DOI: 10.1093/HMG/DDS231
Abstract: Myofibrillar myopathies are a group of muscle disorders characterized by the disintegration of skeletal muscle fibers and formation of sarcomeric protein aggregates. All the proteins known to be involved in myofibrillar myopathies localize to a region of the sarcomere known as the Z-disk, the site at which defects are first observed. Given the common cellular phenotype observed in this group of disorders, it is thought that there is a common mechanism of pathology. Mutations in filamin C, which has several proposed roles in the development and function of skeletal muscle, can result in filamin-related myofibrillar myopathy. The lack of a suitable animal model system has limited investigation into the mechanism of pathology in this disease and the role of filamin C in muscle development. Here, we characterize stretched out (sot), a zebrafish filamin Cb mutant, together with targeted knockdown of zebrafish filamin Ca, revealing fiber dissolution and formation of protein aggregates strikingly similar to those seen in filamin-related myofibrillar myopathies. Through knockdown of both zebrafish filamin C homologues, we demonstrate that filamin C is not required for fiber specification and that fiber damage is a consequence of muscle activity. The remarkable similarities in the myopathology between our models and filamin-related myofibrillar myopathy makes them suitable for the study of these diseases and provides unique opportunities for the investigation of the function of filamin C in muscle and development of therapies.
Publisher: Oxford University Press (OUP)
Date: 06-11-2019
DOI: 10.1093/HMG/DDZ260
Abstract: Dynamin 2 (DNM2) encodes a ubiquitously expressed large GTPase with membrane fission capabilities that participates in the endocytosis of clathrin-coated vesicles. Heterozygous mutations in DNM2 are associated with two distinct neuromuscular disorders, Charcot–Marie–Tooth disease (CMT) and autosomal dominant centronuclear myopathy (CNM). Despite extensive investigations in cell culture, the role of dynamin 2 in normal muscle development is poorly understood and the consequences of DNM2 mutations at the molecular level in vivo are not known. To address these gaps in knowledge, we developed transgenic zebrafish expressing either wild-type dynamin 2 or dynamin 2 with either a CNM or CMT mutation. Taking advantage of the live imaging capabilities of the zebrafish embryo, we establish the localization of wild-type and mutant dynamin 2 in vivo, showing for the first time distinctive dynamin 2 subcellular compartments. Additionally, we demonstrate that CNM-related DNM2 mutations are associated with protein mislocalization and aggregation. Lastly, we define core phenotypes associated with our transgenic mutant fish, including impaired motor function and altered muscle ultrastructure, making them the ideal platform for drug screening. Overall, using the power of the zebrafish, we establish novel insights into dynamin 2 localization and dynamics and provide the necessary groundwork for future studies examining dynamin 2 pathomechanisms and therapy development.
Publisher: Cold Spring Harbor Laboratory
Date: 23-12-2021
DOI: 10.1101/2021.12.22.473918
Abstract: Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation-contraction coupling (ECC). Bi-allelic autosomal recessive mutations in striated muscle enriched protein kinase ( SPEG ) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of Speg knockout mice. Thus, the precise biological role of SPEG in skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb , and spega/spegb ( speg -DKO) mutant lines. We demonstrate that speg -DKO zebrafish faithfully recapitulate multiple phenotypes associated with human CNM, including disruption of the ECC protein machinery, dysregulation of calcium homeostasis during ECC, and impairment of muscle performance. Taking advantage of the availability of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg -DKO with mtm1 -KO and DNM2 -S619L transgenic zebrafish. We observed desmin (DES) accumulation common to all CNM subtypes, and DNM2 upregulation in muscle of both speg -DKO and mtm1 -KO zebrafish. In all, we establish a new model of SPEG -related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies. We created a novel zebrafish speg mutant model of centronuclear myopathy that recapitulates key features of the human disorder and provides insight into pathomechanisms of the disease.
Publisher: The Company of Biologists
Date: 05-2022
DOI: 10.1242/DMM.049437
Abstract: Centronuclear myopathy (CNM) is a congenital neuromuscular disorder caused by pathogenic variation in genes associated with membrane trafficking and excitation–contraction coupling (ECC). Bi-allelic autosomal-recessive mutations in striated muscle enriched protein kinase (SPEG) account for a subset of CNM patients. Previous research has been limited by the perinatal lethality of constitutive Speg knockout mice. Thus, the precise biological role of SPEG in developing skeletal muscle remains unknown. To address this issue, we generated zebrafish spega, spegb and spega spegb (speg-DKO) mutant lines. We demonstrated that speg-DKO zebrafish faithfully recapitulate multiple phenotypes associated with CNM, including disruption of the ECC machinery, dysregulation of calcium homeostasis during ECC and impairment of muscle performance. Taking advantage of zebrafish models of multiple CNM genetic subtypes, we compared novel and known disease markers in speg-DKO with mtm1-KO and DNM2-S619L transgenic zebrafish. We observed Desmin accumulation common to all CNM subtypes, and Dnm2 upregulation in muscle of both speg-DKO and mtm1-KO zebrafish. In all, we establish a new model of SPEG-related CNM, and identify abnormalities in this model suitable for defining disease pathomechanisms and evaluating potential therapies. This article has an associated First Person interview with the joint first authors of the paper.
Publisher: Cold Spring Harbor Laboratory
Date: 05-2021
DOI: 10.1101/2021.04.30.440339
Abstract: Experimental data about known gene functions curated from the primary literature have enormous value for research scientists in understanding biology. Using the Gene Ontology (GO), manual curation by experts has provided an important resource for studying gene function, especially within model organisms. Unprecedented expansion of the scientific literature and validation of the predicted proteins have increased both data value and the challenges of keeping pace. Capturing literature-based functional annotations is limited by the ability of biocurators to handle the massive and rapidly growing scientific literature. Within the community-oriented wiki framework for GO annotation called the Gene Ontology Normal Usage Tracking System (GONUTS), we describe an approach to expand biocuration through crowdsourcing with undergraduates. This multiplies the number of high-quality annotations in international databases, enriches our coverage of the literature on normal gene function, and pushes the field in new directions. From an intercollegiate competition judged by experienced biocurators, Community Assessment of Community Annotation with Ontologies (CACAO), we have contributed nearly 5000 literature-based annotations. Many of those annotations are to organisms not currently well-represented within GO. Over a ten-year history, our community contributors have spurred changes to the ontology not traditionally covered by professional biocurators. The CACAO principle of relying on community members to participate in and shape the future of biocuration in GO is a powerful and scalable model used to promote the scientific enterprise. It also provides undergraduate students with a unique and enriching introduction to critical reading of primary literature and acquisition of marketable skills. The primary scientific literature catalogs the results from publicly funded scientific research about gene function in human-readable format. Information captured from those studies in a widely adopted, machine-readable standard format comes in the form of Gene Ontology annotations about gene functions from all domains of life. Manual annotations based on inferences directly from the scientific literature, including the evidence used to make such inferences, represents the best return on investment by improving data accessibility across the biological sciences. To supplement professional curation, our CACAO project enabled annotation of the scientific literature by community annotators, in this case undergraduates, which resulted in contribution of thousands of validated entries to public resources. These annotations are now being used by scientists worldwide.
Publisher: Springer Science and Business Media LLC
Date: 05-2015
Location: United States of America
No related grants have been discovered for Mo Zhao.