Microenvironmental regulation by fibrillin-1

Gerhard Sengle, Ko Tsutsui, Douglas R. Keene, Sara F. Tufa, Eric J. Carlson, Noe L. Charbonneau, Robert N. Ono, Takako Sasaki, Mary Wirtz, John R. Samples, Liselotte I. Fessler, John H. Fessler, Kiyotoshi Sekiguchi, Susan Hayflick, Lynn Sakai

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.

Original languageEnglish (US)
Article numbere1002425
JournalPLoS Genetics
Volume8
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Weill-Marchesani Syndrome
mutation
Microfibrils
Marfan Syndrome
Mutation
skin (animal)
growth factors
skin
mice
Skin
protein
Intercellular Signaling Peptides and Proteins
collagen
Arachnodactyly
Ectopia Lentis
dissection
homeostasis
Brachydactyly
ultrastructure
extracellular matrix

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Sengle, G., Tsutsui, K., Keene, D. R., Tufa, S. F., Carlson, E. J., Charbonneau, N. L., ... Sakai, L. (2012). Microenvironmental regulation by fibrillin-1. PLoS Genetics, 8(1), [e1002425]. https://doi.org/10.1371/journal.pgen.1002425

Microenvironmental regulation by fibrillin-1. / Sengle, Gerhard; Tsutsui, Ko; Keene, Douglas R.; Tufa, Sara F.; Carlson, Eric J.; Charbonneau, Noe L.; Ono, Robert N.; Sasaki, Takako; Wirtz, Mary; Samples, John R.; Fessler, Liselotte I.; Fessler, John H.; Sekiguchi, Kiyotoshi; Hayflick, Susan; Sakai, Lynn.

In: PLoS Genetics, Vol. 8, No. 1, e1002425, 01.2012.

Research output: Contribution to journalArticle

Sengle, G, Tsutsui, K, Keene, DR, Tufa, SF, Carlson, EJ, Charbonneau, NL, Ono, RN, Sasaki, T, Wirtz, M, Samples, JR, Fessler, LI, Fessler, JH, Sekiguchi, K, Hayflick, S & Sakai, L 2012, 'Microenvironmental regulation by fibrillin-1', PLoS Genetics, vol. 8, no. 1, e1002425. https://doi.org/10.1371/journal.pgen.1002425
Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL et al. Microenvironmental regulation by fibrillin-1. PLoS Genetics. 2012 Jan;8(1). e1002425. https://doi.org/10.1371/journal.pgen.1002425
Sengle, Gerhard ; Tsutsui, Ko ; Keene, Douglas R. ; Tufa, Sara F. ; Carlson, Eric J. ; Charbonneau, Noe L. ; Ono, Robert N. ; Sasaki, Takako ; Wirtz, Mary ; Samples, John R. ; Fessler, Liselotte I. ; Fessler, John H. ; Sekiguchi, Kiyotoshi ; Hayflick, Susan ; Sakai, Lynn. / Microenvironmental regulation by fibrillin-1. In: PLoS Genetics. 2012 ; Vol. 8, No. 1.
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