Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized zebrafish kmt2d null mutants that recapitulate the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development, and cardiac defects. The cardiac phenotype consists of a previously unknown vasculogenesis defect that affects endocardium patterning and, consequently, heart ventricle lumen formation. Additionally, zebrafish kmt2d null mutants have angiogenesis defects depicted by abnormal aortic arch development, hyperactive ectopic blood vessel sprouting, and aberrant patterning of the brain vascular plexus. We demonstrate that zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in endocardial and endothelial cells, including increased protein levels of the Notch transcription factor Rbpj. Our zebrafish Kabuki Syndrome model reveals a regulatory link between the Notch pathway and Kmt2d during endothelium and endocardium patterning and shows that pharmacological inhibition of Notch signaling rebalances Rbpj protein levels and rescues the cardiovascular phenotype by enhancing endothelial and endocardial cell proliferation and stabilizing endocardial patterning. Taken together, these findings demonstrate that Kmt2d regulates vasculogenesis and angiogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
BackgroundThere is ongoing and increasing interest in the commercialization of biospecimen-derived products from Indigenous Peoples. Discourse on benefit-sharing specifically in the context of the commercialization of Indigenous Peoples biospecimens are currently lacking. A better understanding of the potential ethical imperatives is in need of exploration on this emerging topic. This review sought to elucidate through categorization the current discourse in the peer-reviewed literature on the commercialization of Indigenous Peoples' biospecimens from a benefit-sharing perspective.MethodsA scoping review methodology was utilized to perform a search of PubMed, CINAHL, Embase and Google Scholar. A two-stage screening process was used to assess the relevance of any included articles with subsequent manual open coding of articles. Content analysis was applied to identify the main categories and sub-categories within the article data.ResultsThirty-three articles met the inclusion criteria for analysis. Four overarching categories from the included articles were identified regarding the most common discourse on the commercialization of Indigenous Peoples' biospecimens from a benefit-sharing perspective, including: exploitation through biocolonialism, sovereignty and Indigenous rights, ethical considerations for benefit-sharing, and guidelines and standards concerns.ConclusionThis scoping review highlighted the crucial need to keep Indigenous communities at the center of research projects, ensuring any benefits, advancement, and potential commercial profits are returned to communities through clear and ethical agreements. We encourage all research institutions and institutional ethical review bodies to better clarify the collective needs and interests of Indigenous communities while centering their sovereignty and rights within the research process as it pertains to potential biospecimen product commercialization.
Kabuki Syndrome patients have a spectrum of congenital disorders, including congenital heart defects, the primary determinant of mortality. Seventy percent of Kabuki Syndrome patients have mutations in the histone methyl-transferase KMT2D. However, the underlying mechanisms that drive these congenital disorders are unknown. Here, we generated and characterized a zebrafish kmt2d null mutant that recapitulates the cardinal phenotypic features of Kabuki Syndrome, including microcephaly, palate defects, abnormal ear development and cardiac defects. The cardiovascular defects consist of abnormal aortic arches and hypoplastic ventricle, driven by previously unknown aberrant endocardial and endothelial vasculogenesis. We identify a regulatory link between the Notch pathway and Kmt2d during vasculogenesis and show that pharmacological inhibition of Notch signaling rescues the cardiovascular phenotype in zebrafish Kabuki Syndrome. Taken together these findings demonstrate that Kmt2d regulates vasculogenesis, provide evidence for interactions between Kmt2d and Notch signaling in Kabuki Syndrome, and suggest future directions for clinical research.
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