C2 Gerhard Sengle, Matthias Hammerschmidt
Microenvironmental regulation of muscle homeostasis and its role in musculoskeletal diseases
Prof. Dr. Gerhard Sengle
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne
University of Cologne
Zülpicher Str. 47b, 50674 Cologne
Summary
Tissue microenvironments formed by extracellular matrix networks play an important role in regulating tissue structure and function. Extracellular microfibrillar networks (EMFN) involving fibrillins (fibrillin-1 and -2), and hemicentins (hemicentin-1 and -2) are of particular interest in this regard since they surround cells in close proximity to basement membranes, thereby guiding proper morphology and functional behavior of specialized cell types. Hemicentins belong to the fibulin family of secreted glycoproteins, where the best characterized members (fibulin-2, -4, and -5) are targeted to fibrillins. Combined loss of hemicentin-1 and -2 function in zebrafish embryos leads to muscle dystrophy very similar to the defects of zebrafish mutants lacking fibrillin-2, implying a common underlying genetic pathway. As fibrillins and hemicentins show overlapping expression and localization patterns, our hypothesis is that EMFN composed of fibrillins and hemicentins function in concert to control muscle, cartilage, and bone homeostasis and / or regeneration. We therefore want to investigate how the two networks interact with each other and with (other) basement membrane and cell surface components, and whether they serve as structural platform for the concentration and presentation of connective tissue growth factors.Publications
Elezagic D, Mörgelin M, Hermes G, Hamprecht A, Sengle G, Lau D, Höllriegl S, Wagener R, Paulsson M, Streichert T, Klatt AR 2019 Antimicrobial peptides derived from the cartilage.-specific C-type Lectin Domain Family 3 Member A (CLEC3A) - potential in the prevention and treatment of septic arthritis. Osteoarthritis Cartilage 27(10):1564-1573.
Mayorca-Guiliani AE, Willacy O, Madsen CD, Rafaeva M, Heumüller SE, Bock F, Sengle G, Koch M, Imhof T, Zaucke F, Wagener R, Sasaki T, Erler JT, Reuten R 2019 Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat Protoc. 14(12):3395-3425.
Riessland M, Kaczmarek A, Schneider S, Swoboda KJ, Löhr H, Bradler C, Grysko V, Dimitriadi M, Hosseinibarkooie S, Torres-Benito L, Peters M, Upadhyay A, Biglari N, Kröber S, Hölker I, Garbes L, Gilissen C, Hoischen A, Nürnberg G, Nürnberg P, Walter M, Rigo F, Bennett CF, Kye MJ, Hart AC, Hammerschmidt M, Kloppenburg P, Wirth B 2017 Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis. Am J Hum Genet 100(2): 297-315.
Schiavinato A, Keene DR, Imhof T, Doliana R, Sasaki T, Sengle G 2017 Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. Sci Rep 7(1):5526.
Jeradi S, Hammerschmidt M 2016 Retinoic acid-induced premature osteoblast-to-preosteocyte transitioning has multiple effects on calvarial development. Development 143(7):1205-16.
Schiavinato A, Keene DR, Wohl AP, Corallo D, Colombatti A, Wagener R, Paulsson M, Bonaldo P, Sengle G 2016 Targeting of EMILIN-1 and EMILIN-2 to fibrillin microfibrils facilitates their incorporation into the extracellular matrix. J Invest Dermatol 136(6):1150-60.
Wohl AP, Troilo H, Collins RF, Baldock C, Sengle G 2016 Extracellular regulation of bone morphogenetic protein activity by the microfibril component fibrillin-1. J Biol Chem 291(24):12732-12746.
Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY 2015 Abnormal activation of BMP signaling causes myopathy in Fbn2 null mice. PLoS Genet 11(6):e1005340.
Richardson R, Gebauer JM, Zhang JL, Kobbe B, Keene DR, Karlson KR, Richetti S, Wohl AP, Sengle G, Neiss WF, Paulsson M, Hammerschmidt M*, Wagener R* 2014 AMACO is a novel component of the basement membrane associated Fraser complex. J Invest Dermatol 134:1313-1322. (*joint corresponding authors).
Feitosa NM, Zhang J, Carney TJ, Metzger M, Korzh V, Bloch W, Hammerschmidt M 2012 Hemicentin2 and fibulin1 are required for epidermal-dermal junction formation and fin mesenchymal cell migration during zebrafish development. Dev Biol 369(2):235-248.
Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, Ono RN, Sasaki T, Wirtz MK, Samples JR, Fessler LI, Fessler JH, Sekiguchi K, Hayflick SJ, Sakai LY 2012 Microenvironmental regulation by fibrillin-1. PLoS Genet 8(1):e1002425.
Carney TJ, Feitosa N, Sonntag C, Slanchev K, Kluger J, Kiyozumi D, Gebauer J, Talbot J, Kimmel CB, Sekiguchi K, Wagener R, Schwarz R, Ingham PI, Hammerschmidt M 2010 Genetic analysis of fin development in zebrafish identifies Furin and Hemicentin1 as potential novel Fraser Syndrome disease genes. PLoS Genet 6(4):e1000907.
