# Musculoskeletal growth and homeostasis: does extracellular fibrillin matrix regulate Notch signaling components?

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $169,400

## Abstract

PROJECT SUMMARY
 Autosomal dominant mutations in FBN1, the gene for fibrillin-1, cause the Marfan syndrome as well as
the acromelic dysplasias such as Weill-Marchesani syndrome, geleophysic dysplasia, and acromicric
dysplasia. These genetic disorders provide evidence that fibrillin-1 controls musculoskeletal growth and
homeostasis. However, it is unknown why most of the mutations in FBN1 cause tall stature, arachnodactyly,
hypermobile joints, and poor musculature (typical features of the Marfan syndrome) while other mutations in
FBN1 result in the opposite features of short stature, brachydactyly, stiff joints, and hypermusculature (typical
of the acromelic dysplasias). Because fibrillins target and sequester growth factors such as Bone
Morphogenetic Proteins (BMPs) and the large latent TGFβ complexes, the yin yang musculoskeletal features
in the fibrillinopathies are thought to reflect different effects of mutations on growth factors. Within this context,
there remain multiple mechanisms to be elucidated in both time and space. The long-term goal of this work is
to learn how cellular interactions with fibrillin-1 coordinate growth factor signaling during postnatal
musculoskeletal growth and pathogenesis of disease.
 The short-term goal of this application is to test the hypothesis that novel interactions between fibrillin-1
and Notch signaling components are required for postnatal musculoskeletal growth and homeostasis.
Biochemical data indicate that fibrillin-1 binds to Notch signaling components with affinities similar to those
measured for Notch-Jagged interactions. Because conventional concepts of Notch signaling are based on
cell-cell interactions between Notch receptors on one cell and Notch ligands (like Jagged or Delta) on an
adjacent cell, our results showing interactions between Notch signaling components and fibrillin, an
extracellular matrix molecule, are truly ground-breaking. To determine the in vivo impact of these interactions,
we will use Fbn1 targeted mice in which the binding site for Notch signaling components has been deleted.
 This R21 application is “exploratory/developmental” in that it will explore/develop our exciting in vitro
findings of interactions between fibrillin and Notch signaling components. These interactions will be tested in
vivo in a novel mouse model which can be used to further advantage in the future. We expect that successful
completion of our proposed studies will open the door to a new paradigm for extracellular control of Notch
signaling. In addition, we expect to generate homozygous mouse models with musculoskeletal phenotypes
related to those found in heterozygous humans (for example, shortened long bones, kyphosis/scoliosis,
abnormal musculature), but in exaggerated form, and especially useful to begin investigations of molecular
interactions that cause these phenotypes. In the future, others in the scientific community will have the
opportunity to elucidate how fibrillin matrix participates in th...

## Key facts

- **NIH application ID:** 10057700
- **Project number:** 1R21AR076559-01A1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** LYNN Y SAKAI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,400
- **Award type:** 1
- **Project period:** 2020-07-08 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057700

## Citation

> US National Institutes of Health, RePORTER application 10057700, Musculoskeletal growth and homeostasis: does extracellular fibrillin matrix regulate Notch signaling components? (1R21AR076559-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10057700. Licensed CC0.

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