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Publications (10 of 29) Show all publications
Habicher, J., Varshney, G. K., Waldmann, L., Snitting, D., Allalou, A., Zhang, H., . . . Ledin, J. (2022). Chondroitin/dermatan sulfate glycosyltransferase genes are essential for craniofacial development. PLOS Genetics, 18(2), Article ID e1010067.
Open this publication in new window or tab >>Chondroitin/dermatan sulfate glycosyltransferase genes are essential for craniofacial development
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2022 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 18, no 2, article id e1010067Article in journal (Refereed) Published
Abstract [en]

Chondroitin/dermatan sulfate (CS/DS) proteoglycans are indispensable for animal development and homeostasis but the large number of enzymes involved in their biosynthesis have made CS/DS function a challenging problem to study genetically. In our study, we generated loss-of-function alleles in zebrafish genes encoding CS/DS biosynthetic enzymes and characterized the effect on development in single and double mutants. Homozygous mutants in chsy1, csgalnact1a, csgalnat2, chpfa, ust and chst7, respectively, develop to adults. However, csgalnact1a-/- fish develop distinct craniofacial defects while the chsy1-/- skeletal phenotype is milder and the remaining mutants display no gross morphological abnormalities. These results suggest a high redundancy for the CS/DS biosynthetic enzymes and to further reduce CS/DS biosynthesis we combined mutant alleles. The craniofacial phenotype is further enhanced in csgalnact1a-/-;chsy1-/- adults and csgalnact1a-/-;csgalnact2-/- larvae. While csgalnact1a-/-;csgalnact2-/- was the most affected allele combination in our study, CS/DS is still not completely abolished. Transcriptome analysis of chsy1-/-, csgalnact1a-/- and csgalnact1a-/-;csgalnact2-/- larvae revealed that the expression had changed in a similar way in the three mutant lines but no differential expression was found in any of fifty GAG biosynthesis enzymes identified. Thus, zebrafish larvae do not increase transcription of GAG biosynthesis genes as a consequence of decreased CS/DS biosynthesis. The new zebrafish lines develop phenotypes similar to clinical characteristics of several human congenital disorders making the mutants potentially useful to study disease mechanisms and treatment.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2022
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-473635 (URN)10.1371/journal.pgen.1010067 (DOI)001004241700001 ()35192612 (PubMedID)
Funder
Science for Life Laboratory, SciLifeLab
Note

Correction in: The PLOS Genetics, vol. 18, issue 5, Article no e1010242.

DOI: 10.1371/journal.pgen.1010242

Available from: 2022-04-29 Created: 2022-04-29 Last updated: 2023-10-10Bibliographically approved
Arnold, H., Panara, V., Hussmann, M., Gorniok, B. F., Skoczylas, R., Ranefall, P., . . . Koltowska, K. (2022). mafba and mafbb differentially regulate lymphatic endothelial cell migration in topographically distinct manners. Cell Reports, 39(12), Article ID 110982.
Open this publication in new window or tab >>mafba and mafbb differentially regulate lymphatic endothelial cell migration in topographically distinct manners
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2022 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 39, no 12, article id 110982Article in journal (Refereed) Published
Abstract [en]

Lymphangiogenesis, formation of lymphatic vessels from pre-existing vessels, is a dynamic process that requires cell migration. Regardless of location, migrating lymphatic endothelial cell (LEC) progenitors probe their surroundings to form the lymphatic network. Lymphatic-development regulation requires the transcription factor MAFB in different species. Zebrafish Mafba, expressed in LEC progenitors, is essential for their migration in the trunk. However, the transcriptional mechanism that orchestrates LEC migration in different lymphatic endothelial beds remains elusive. Here, we uncover topographically different requirements of the two paralogs, Mafba and Mafbb, for LEC migration. Both mafba and mafbb are necessary for facial lymphatic development, but mafbb is dispensable for trunk lymphatic development. On the molecular level, we demonstrate a regulatory network where Vegfc-Vegfd-SoxF-Mafba-Mafbb is essential in facial lymphangiogenesis. We identify that mafba and mafbb tune the directionality of LEC migration and vessel morphogenesis that is ultimately necessary for lymphatic function.

Place, publisher, year, edition, pages
ElsevierElsevier BV, 2022
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-481695 (URN)10.1016/j.celrep.2022.110982 (DOI)000826780900003 ()35732122 (PubMedID)
Available from: 2022-08-16 Created: 2022-08-16 Last updated: 2024-01-17Bibliographically approved
Waldmann, L., Leyhr, J., Zhang, H., Allalou, A., Öhman, C. & Haitina, T. (2022). The Role of Gdf5 in the Development of the Zebrafish Fin Endoskeleton. Developmental Dynamics, 251(9), 1535-1549
Open this publication in new window or tab >>The Role of Gdf5 in the Development of the Zebrafish Fin Endoskeleton
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2022 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 251, no 9, p. 1535-1549Article in journal (Refereed) Published
Abstract [en]

The development of the vertebrate skeleton requires a complex interaction of multiple factors to facilitate correct shaping and positioning of bones and joints. Growth and differentiation factor 5 (Gdf5), a member of the transforming growth factor-beta family (TGF-beta) is involved in patterning appendicular skeletal elements including joints. Expression of gdf5 in zebrafish has been detected within the first pharyngeal arch jaw joint, fin mesenchyme condensations and segmentation zones in median fins, however little is known about the functional role of Gdf5 outside of Amniota. 

We generated CRISPR/Cas9 knockout of gdf5 in zebrafish and analysed the resulting phenotype at different developmental stages. Homozygous gdf5 mutant zebrafish display truncated median fin endoskeletal elements and loss of posterior radials in the pectoral fins. 

These findings are consistent with phenotypes observed in human and mouse appendicular skeleton in response to Gdf5 knockout, suggesting a broadly conserved role for Gdf5 in Osteichthyes.

Place, publisher, year, edition, pages
John Wiley & SonsWiley, 2022
Keywords
gdf5, fin, joints, zebrafish, appendicular skeleton, CRISPR/Cas9 mutant
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-430383 (URN)10.1002/dvdy.399 (DOI)000678743100001 ()
Funder
Swedish Research Council, 621-2012-4673Science for Life Laboratory, SciLifeLab
Available from: 2021-01-08 Created: 2021-01-08 Last updated: 2024-05-07Bibliographically approved
Waldmann, L., Leyhr, J., Zhang, H., Öhman, C., Allalou, A. & Haitina, T. (2021). The broad role of Nkx3.2 in the development of the zebrafish axial skeleton. PLOS ONE, 16(8), Article ID e0255953.
Open this publication in new window or tab >>The broad role of Nkx3.2 in the development of the zebrafish axial skeleton
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2021 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 8, article id e0255953Article in journal (Refereed) Published
Abstract [en]

The transcription factor Nkx3.2 (Bapx1) is an important chondrocyte maturation inhibitor. Previous Nkx3.2 knockdown and overexpression studies in non-mammalian gnathostomes have focused on its role in primary jaw joint development, while the function of this gene in broader skeletal development is not fully described. We generated a mutant allele of nkx3.2 in zebrafish with CRISPR/Cas9 and applied a range of techniques to characterize skeletal phenotypes at developmental stages from larva to adult, revealing loss of the jaw joint, fusions in bones of the occiput, morphological changes in the Weberian apparatus, and the loss or deformation of bony elements derived from basiventral cartilages of the vertebrae. Axial phenotypes are reminiscent of Nkx3.2 knockout in mammals, suggesting that the function of this gene in axial skeletal development is ancestral to osteichthyans. Our results highlight the broad role of nkx3.2 in zebrafish skeletal development and its context-specific functions in different skeletal elements.

Place, publisher, year, edition, pages
Public Library of Science (PLoS)Public Library of Science (PLoS), 2021
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-455491 (URN)10.1371/journal.pone.0255953 (DOI)000686373300086 ()34411150 (PubMedID)
Funder
Swedish Research Council, 621-2012-4673
Available from: 2021-10-18 Created: 2021-10-18 Last updated: 2024-01-15Bibliographically approved
del Pozo, A., Manuel, R., Iglesias Gonzalez, A. B., Koning, H. K., Habicher, J., Zhang, H., . . . Boije, H. (2020). Behavioral Characterization of dmrt3a Mutant Zebrafish Reveals Crucial Aspects of Vertebrate Locomotion through Phenotypes Related to Acceleration. eNeuro, 7(3), Article ID 0047-20.2020.
Open this publication in new window or tab >>Behavioral Characterization of dmrt3a Mutant Zebrafish Reveals Crucial Aspects of Vertebrate Locomotion through Phenotypes Related to Acceleration
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2020 (English)In: eNeuro, E-ISSN 2373-2822, Vol. 7, no 3, article id 0047-20.2020Article in journal (Refereed) Published
Abstract [en]

Vertebrate locomotion is orchestrated by spinal interneurons making up a central pattern generator. Proper coordination of activity, both within and between segments, is required to generate the desired locomotor output. This coordination is altered during acceleration to ensure the correct recruitment of muscles for the chosen speed. The transcription factor Dmrt3 has been proposed to shape the patterned output at different gaits in horses and mice. Here, we characterized dmrt3a mutant zebrafish, which showed a strong, transient, locomotor phenotype in developing larvae. During beat-and-glide swimming, mutant larvae showed fewer and shorter movements with decreased velocity and acceleration. Developmental compensation likely occurs as the analyzed behaviors did not differ from wild-type at older larval stages. However, analysis of maximum swim speed in juveniles suggests that some defects persist within the mature locomotor network of dmrt3a mutants. Our results reveal the pivotal role Dmrt3 neurons play in shaping the patterned output during acceleration in vertebrates.

Keywords
central pattern generator, Danio rerio, gait, locomotion, spinal cord, wt1
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-424650 (URN)10.1523/ENEURO.0047-20.2020 (DOI)000571515500007 ()32357958 (PubMedID)
Funder
Swedish Research Council
Available from: 2020-11-09 Created: 2020-11-09 Last updated: 2023-10-09Bibliographically approved
von der Heyde, B., Emmanouilidou, A., Mazzaferro, E., Vicenzi, S., Höijer, I., Klingström, T., . . . den Hoed, M. (2020). Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach. Scientific Reports, 10(1)
Open this publication in new window or tab >>Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1Article in journal (Refereed) Published
Abstract [en]

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30 s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25 mu M ivabradine-an open channel blocker of HCNs-for 24 h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-419787 (URN)10.1038/s41598-020-68567-1 (DOI)000550057200144 ()32678143 (PubMedID)
Available from: 2020-09-17 Created: 2020-09-17 Last updated: 2022-09-15Bibliographically approved
Zhang, H., Waldmann, L., Manuel, R., Boije, H., Haitina, T. & Allalou, A. (2020). zOPT: an open source optical projection tomography system and methods for rapid 3D zebrafish imaging. Biomedical Optics Express, 11(8), 4290-4305
Open this publication in new window or tab >>zOPT: an open source optical projection tomography system and methods for rapid 3D zebrafish imaging
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2020 (English)In: Biomedical Optics Express, E-ISSN 2156-7085, Vol. 11, no 8, p. 4290-4305Article in journal (Refereed) Published
Abstract [en]

Optical projection tomography (OPT) is a 3D imaging alternative to conventional microscopy which allows imaging of millimeter-sized object with isotropic micrometer resolution. The zebrafish is an established model organism and an important tool used in genetic and chemical screening. The size and optical transparency of the embryo and larva makes them well suited for imaging using OPT. Here, we present an open-source implementation of an OPT platform, built around a customized sample stage, 3D-printed parts and open source algorithms optimized for the system. We developed a versatile automated workflow including a two-step image processing approach for correcting the center of rotation and generating accurate 3D reconstructions. Our results demonstrate high-quality 3D reconstruction using synthetic data as well as real data of live and fixed zebrafish. The presented 3D-printable OPT platform represents a fully open design, low-cost and rapid loading and unloading of samples. Our system offers the opportunity for researchers with different backgrounds to setup and run OPT for large scale experiments, particularly in studies using zebrafish larvae as their key model organism.

Place, publisher, year, edition, pages
The Optical Society, 2020
National Category
Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-419799 (URN)10.1364/BOE.393519 (DOI)000577451600016 ()32923043 (PubMedID)
Funder
Science for Life Laboratory, SciLifeLab
Available from: 2020-09-16 Created: 2020-09-16 Last updated: 2023-02-17Bibliographically approved
Gudmundsson, S., Wilbe, M., Gorniok, B. F., Molin, A.-M., Ekvall, S., Johansson, J., . . . Bondeson, M.-L. (2019). TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish. Scientific Reports, 9, Article ID 10730.
Open this publication in new window or tab >>TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
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2019 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 10730Article in journal (Refereed) Published
Abstract [en]

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

Keywords
taf1, intellectual disability, zebrafish
National Category
Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379358 (URN)10.1038/s41598-019-46632-8 (DOI)000476874600028 ()31341187 (PubMedID)
Funder
EU, European Research Council, 241995
Note

Title in Thesis list of papers: TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2022-09-15Bibliographically approved
Eimon, P. M., Ghannad-Rezaie, M., De Rienzo, G., Allalou, A., Wu, Y., Gao, M., . . . Yanik, M. F. (2018). Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects.. Nature Communications, 9(1), Article ID 219.
Open this publication in new window or tab >>Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects.
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2018 (English)In: Nature Communications, E-ISSN 2041-1723, Nature Communications, ISSN 2041-1723, EISSN 2041-1723, ISSN 2041-1723, Vol. 9, no 1, article id 219Article in journal (Refereed) Published
Abstract [en]

Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson's disease. To determine whether drugs that enhance BAP complexity produces positive outcomes, we used light pulses to trigger seizures in a model of Dravet syndrome, an intractable genetic epilepsy. The highest-ranked compounds identified by BAP analysis exhibit far greater anti-seizure efficacy and fewer side effects during subsequent in-depth behavioral assessment. This high correlation with behavioral outcomes illustrates the power of brain activity pattern-based screens and identifies novel therapeutic candidates with minimal side effects.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-397347 (URN)10.1038/s41467-017-02404-4 (DOI)29335539 (PubMedID)
Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2023-03-28Bibliographically approved
Allalou, A., Wu, Y., Ghannad-Rezaie, M., Eimon, P. M. & Yanik, M. F. (2017). Automated deep-phenotyping of the vertebrate brain. eLIFE, 6, Article ID e23379.
Open this publication in new window or tab >>Automated deep-phenotyping of the vertebrate brain
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2017 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 6, article id e23379Article in journal (Refereed) Published
National Category
Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-324637 (URN)10.7554/eLife.23379 (DOI)000401797500001 ()
Available from: 2017-04-13 Created: 2017-06-16 Last updated: 2017-11-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-4028-8443

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