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The role of Six1 in muscle progenitor cells and the establishment of fast-twitch muscle fibres
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).ORCID iD: 0000-0002-6098-0237
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myogenesis is the process of skeletal muscle tissue formation where committed muscle progenitor cells differentiate into skeletal muscle fibres. Depending on the instructive cues the muscle progenitor cells receive they will differentiate into specific fibre types with different properties. The skeletal muscle fibres can be broadly classified as fast-twitch fibres or slow-twitch fibres, based on their contractile speed. However, subgroups of fast- and slow-twitch fibres with different metabolic properties, endurance and different isoforms of sarcomeric components have also been identified, adding complexity to the process of muscle tissue patterning. The skeletal muscle tissue has the capacity to regenerate throughout life. Upon muscle tissue damage muscle satellite cells are recruited to the area of injury where they proliferate and either form new fibres similar to those damaged, or fuse with existing fibres.

This thesis aims to investigate the process of muscle progenitor cell proliferation and differentiation, as well as the fast-twitch fibre formation and muscle tissue patterning in the zebrafish embryo.

I present results identifying the previously uncharacterised gene myl1, encoding an alkali-like myosin light chain, which is specifically expressed in fast-twitch muscle progenitors before fibre formation. Furthermore, I introduce data showing that the transcription factor six1 is expressed in Pax7+ muscle progenitor cells, which has been reported to contribute to part of the fast-twitch muscle tissue as well as to a pool of quiescent muscle satellite cells. With support from the presented data, I hypothesise that six1 keeps the Pax7+ muscle progenitor cells in a proliferative state and consequently prevents them from differentiating into muscle fibres. In addition, I demonstrate that the zebrafish fast-twitch muscle fibres can be divided into different subgroups that express unique forms of fast myosin heavy chain genes along the anterior-posterior (head-tail) axis, and that this subspecification depends on a balance between RA and Wnt signalling.

Collectively I propose a previously unknown role for Six1 in zebrafish Pax7+ muscle progenitor cell proliferation and differentiation. Furthermore, I present novel data suggesting that distinct regions of the zebrafish body musculature are composed of different fast-twitch fibre types, and that this regionalisation is conserved in adult zebrafish.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2014. , 47 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1684
Keyword [en]
Myogenesis, zebrafish, muscle fibre, patterning, fmyhc, myl1, Six1, Pax7
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:umu:diva-95849ISBN: 978-91-7601-161-4 (print)OAI: oai:DiVA.org:umu-95849DiVA: diva2:761335
Public defence
2014-12-05, Hörsal B, Unod T9, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2014-11-14 Created: 2014-11-06 Last updated: 2014-11-14Bibliographically approved
List of papers
1. Alkali-like myosin light chain-1 (myl1) is an early marker for differentiating fast muscle cells in zebrafish
Open this publication in new window or tab >>Alkali-like myosin light chain-1 (myl1) is an early marker for differentiating fast muscle cells in zebrafish
2011 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 240, no 7, 1856-1863 p.Article in journal (Refereed) Published
Abstract [en]

During myogenesis, muscle precursors become divided into either fast- or slow-twitch fibres, which in the zebrafish occupy distinct domains in the embryo. Genes encoding sarcomeric proteins specific for fast or slow fibres are frequently used as lineage markers. In an attempt to identify and evaluate early definitive markers for cells in the fast-twitch pathway, we analysed genes encoding proteins contributing to the fast sarcomeric structures. The previously uncharacterized zebrafish alkali-like myosin light chain gene (myl1) was found to be expressed exclusively in cells in the fast-twitch pathway initiated at an early stage of fast fibre differentiation. Myl1 was expressed earlier, and in a more fibre type restricted manner, than any of the previously described and frequently used fast myosin light and heavy chain and troponin muscle markers mylz2, mylz3, tnni2, tnnt3a, fMyHC1.3. In summary, this study introduces a novel marker for early differentiating fast muscle cells.

Place, publisher, year, edition, pages
John Wiley & Sons, 2011
Keyword
alkali-like myosin light chain-1;zebrafish;fast muscle cells
National Category
Developmental Biology
Identifiers
urn:nbn:se:umu:diva-51586 (URN)10.1002/dvdy.22677 (DOI)000292155800020 ()21674687 (PubMedID)
Available from: 2012-01-27 Created: 2012-01-27 Last updated: 2017-12-08Bibliographically approved
2. Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish
Open this publication in new window or tab >>Six1 regulates proliferation of Pax7-positive muscle progenitors in zebrafish
2013 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 8, 1868-1880 p.Article in journal (Refereed) Published
Abstract [en]

In the embryonic zebrafish, skeletal muscle fibres are formed from muscle progenitors in the paraxial mesoderm. The embryonic myotome is mostly constituted of fast-twitch-specific fibres, which are formed from a fast-specific progenitor cell pool. The most lateral fraction of the fast domain in the myotome of zebrafish embryos derives from the Pax7-positive dermomyotome-like cells. In this study, we show that two genes, belonging to the sine oculus class 1 (six1) genes (six1a and six1b), are both essential for the regulation of Pax7(+) cell proliferation and, consequently, in their differentiation during the establishment of the zebrafish dermomyotome. In both six1a and six1b morphant embryos, Pax7(+) cells are initially formed but fail to proliferate, as detected by reduced levels of the proliferation marker phosphohistone3 and reduced brdU incorporation. In congruence, overexpression of six1a or six1b leads to increased Pax7(+) cell number and reduced or alternatively delayed fibre cell differentiation. Bone morphogenetic protein signalling has previously been suggested to inhibit differentiation of Pax7(+) cells in the dermomyotome. Here we show that the remaining Pax7(+) cells in six1a and six1b morphant embryos also have significantly reduced pSmad1/5/8 levels and propose that this leads to a reduced proliferative activity, which may result in a premature differentiation of Pax7(+) cells in the zebrafish dermomyotome. In summary, we show a mechanism for Six1a and Six1b in establishing the Pax7(+) cell derived part of the fast muscle and suggest new important roles for Six1 in the regulation of the Pax7(+) muscle cell population through pSmad1/5/8 signalling.

Place, publisher, year, edition, pages
Cambridge, England: Company of Biologists Ltd, 2013
Keyword
Six1, Pax7, pSMAD 1/5/8, Dermomyotome, Myogenesis, Six1a, Six1b
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-73583 (URN)10.1242/jcs.119917 (DOI)000318975700015 ()
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2017-12-06Bibliographically approved
3. Differential regulation of myosin heavy chains defines new muscle domains in zebrafish
Open this publication in new window or tab >>Differential regulation of myosin heavy chains defines new muscle domains in zebrafish
Show others...
2014 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 8, 1384-1395 p.Article in journal (Refereed) Published
Abstract [en]

Numerous muscle lineages are formed during myogenesis within both slow-and fast-specific cell groups. In this study, we show that six fast muscle-specific myosin heavy chain genes have unique expression patterns in the zebrafish embryo. The expression of tail-specific myosin heavy chain (fmyhc2.1) requires wnt signaling and is essential for fast muscle organization within the tail. Retinoic acid treatment results in reduced wnt signaling, which leads to loss of the fmyhc2.1 domain. Retinoic acid treatment also results in a shift of muscle identity within two trunk domains defined by expression of fmyhc1.2 and fmyhc1.3 in favor of the anteriormost myosin isoform, fmyhc1.2. In summary, we identify new muscle domains along the anteroposterior axis in the zebrafish that are defined by individual nonoverlapping, differentially regulated expression of myosin heavy chain isoforms.

Place, publisher, year, edition, pages
American Society for Cell Biology, 2014
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92681 (URN)10.1091/mbc.E13-08-0486 (DOI)000339649400017 ()24523292 (PubMedID)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved

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