Microenvironmental Regulation by Fibrillin-1

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.

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

“…6 Although Weill-Marchesani patients are opposite to Marfan patients in outward appearance, the syndromes share a common molecular mechanism, which is defective fibrillin-1 microfibrils. 33,73,77 Further supporting a role for ADAMTS10 in microfibril function, co-localization of ADAMTS10 and fibrillin-1 has been shown by immunohistochemistry of human skin 33,73 and ADAMTS10 has been shown to promote microfibril formation in cell culture. 73 Specific and high-affinity binding of ADAMTS10 to fibrillin-1 has been demonstrated by affinity blotting assays, affinity pull-down assays, and surface plasmon resonance.…”

“…28 While important, integrin activation with LAP does not apply to TGFb2 activation because it does not have an RGD domain in its LAP, unlike the other TGFbs. A critical role for microfibrils in TGFb activation is suggested by a number of diseases that have chronic activation of TGFb signaling associated with mutations in fibrillin-1 or other microfibril-related diseases, including Marfan syndrome, [29][30][31][32] Weill-Marchesani syndrome, 33 acromicric dysplasia, 34 geleophysic dysplasia, 34,35 congenital scleroderma, 36 and cutis laxa. 37,38 …”

“…73 Specific and high-affinity binding of ADAMTS10 to fibrillin-1 has been demonstrated by affinity blotting assays, affinity pull-down assays, and surface plasmon resonance. 33,73 The binding site on fibrillin-1 for ADAMTS10 overlaps with the binding site for other ADAMTS proteins, 33 suggesting competition for the fibrillin-1 binding site or complex formation with other microfibril-associated proteins.…”

Copy number variants in patients with short stature

“…Several arguments are in favor of a role of ADAMTS17 in growth regulation (for summary, see Table 3), including: (1) significant association with height in population GWAS; 1 (2) a short child with a similar terminal deletion in the DECIPHER database; (3) significant association with size in a GWAS in the domestic dog; 29 (4) human mutations in ADAMTS17 causing the acromelic chondrodysplasia Weill-Marchesani-like syndrome (OMIM #277600 and #608328); [30][31][32][33] and (5) association of members of the ADAMTSL/ADAMTS family with the modulation of fibrillin-1 function. 31,33 Unfortunately, expression of the rodent homolog of ADAMTS17 could not be investigated, because the gene was not represented on the microarrays used. Besides ADAMTS17, this deletion contains three other genes, ALDH1A3, LRRK1 and CHSY1, that might be implicated in short stature.…”

“…39 Case II.17, described previously, 12 carries a duplication of 3p12.3 containing part of ROBO2, encoding a receptor for SLIT2 and probably SLIT1, thought to function in axon guidance and cell migration. 40 Case II.21, born SGA, length À3.7 SDS and head circumference À3.1 SDS presented with clinodactily, a protruded [30][31][32][33] Associated with fibrillin-1 function. 31,33 Aldh1a3 and Lrrk1 higher expressed in murine GP; Chsy1 highly expressed in HZ and downregulated with age.…”