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Comparative morphological, metabolic and transcriptome analyses in elmo1-/-, elmo2-/- and elmo3-/- zebrafish mutants

Boger, Mike

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The engulfment and cell motility (ELMO) proteins are cytoplasmic adaptor proteins which are evolutionary conserved in several organisms. In higher vertebrates the ELMO protein family consists of the three paralogs ELMO1, ELMO2 and ELMO3. All three ELMO proteins regulate the activity of the Rac family small GTPase 1 (RAC1). As RAC1 regulators, individual ELMO proteins facilitate basic and major cell functions such as cytoskeleton organization, cell migration, phagocytosis, the engulfment of apoptotic cells and myoblast fusion. Several studies have shown that the ELMO proteins are involved in a variety of cellular and developmental processes and linked to multiple diseases, such as cancer, diabetes mellitus, inflammatory bowel disease and developmental disorders. However, the individual functions of ELMO1, ELMO2 and ELMO3 are hardly understood and since barely any studies cover comparative data about all three ELMO proteins, it is mostly unknown whether the Elmo proteins have similar functions and act redundantly or not. To address this question, elmo1-/-, elmo2-/- and elmo3-/- knockout zebrafish were generated using the CRISPR/Cas9 technique and with these mutants a comprehensive comparison of the phenotypic changes in organ morphology, transcriptome and metabolome was performed. The main results were decreased fasting and increased postprandial blood glucose levels in adult elmo1-/-, as well as a decreased vascular formation in the adult retina of elmo1-/-, but an increased vascular formation in the adult retina of elmo3-/- zebrafish. The comparison provided few similarities between the knockout lines, as increased Bowman space areas in adult elmo1-/- and elmo2-/- kidneys, an increased hyaloid vessel diameter in elmo1-/- and elmo3-/- and a transcriptional downregulation of the vascular development in elmo1-/-, elmo2-/-, and elmo3-/- zebrafish larvae. Despite that, elmo1-/-, elmo2-/-, and elmo3-/- zebrafish exhibited several distinct changes in the vascular and glomerular structure, as well as in the metabolome and the transcriptome. Especially, elmo3-/- zebrafish showed extensive differences due to a strong transcriptional dysregulation in larvae and an impaired survivability. Together, the data demonstrate that the three zebrafish Elmo proteins regulate not only similar but many divergent biological processes and mechanisms and show a low functional redundancy.

Document type: Dissertation
Supervisor: Kroll, Prof. Dr. Jens
Place of Publication: Heidelberg
Date of thesis defense: 10 November 2022
Date Deposited: 23 Nov 2022 11:02
Date: 2022
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Medizinische Fakultät Mannheim > Zentrum für Biomedizin und Medizintechnik (CBTM)
DDC-classification: 000 Generalities, Science
500 Natural sciences and mathematics
610 Medical sciences Medicine
Controlled Keywords: Biologie, Biowissenschaften
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