New findings from targeted gene inactivation studies in mice reveal that the extracellular matrix protein fibulin-1 (Fbln1) is required for normal development of the cardiac outflow tract (OFT), pharyngeal glands, cranial nerves and bones of the skull. The developmental anomalies displayed by mice deficient in Fbln1 recapitulate many of the anomalies associated with 22q11 deletion/DiGeorge syndrome (DGS), which occurs with a frequency of 1:4000 human births. The similarity in phenotypes between Fbln1-deficient mice and DGS humans suggests that Fbln1, although located outside of the 22q11 deletion region, is a modifier of the pathway that is dysfunctional in DGS. The molecular pathway of DGS has not been fully elucidated. Key components are the transcription factor Tbx1, Fgf8 and intermediates of the Fgf8 signaling pathway. Several lines of evidence support the hypothesis that Fbln1 regulates this pathway. DNA microarray analysis indicates that Fbln1 is required for expression of forkhead box transcription factors that regulate expression of both Tbx1 and Fgf8 in pharyngeal arch regions including the secondary heart field (SHF). qPCR analysis shows that Tbx1 expression is significantly decreased in pharyngeal arch-containing tissues from Fbln1 null embryos. We also find that Fbln1 interacts with Fgf8 and inhibits Fgf8-mediated activation of the Map kinase-signaling pathway. These observations together with findings that Fbln1 is expressed along pathways of NCC migration, that it can act as a regulator of cell guidance and motility and that it interacts and modulates proteolysis of the proteoglycan versican, a regulator of NCC migration, lead to the following hypothesis: Fbln1 is a key component of the mechanism by which Fgf8 influences NCC-dependent development of the pharyngeal arch and the formation of derivative structures including the OFT, pharyngeal glands and craniofacial structures. To test this hypothesis and gain mechanistic understanding there are three specific aims: 1) Define the effects of Fbln1 on the Fgf8 signaling pathway;2) Identify genetic interactions between Fbln1 and Tbx1 and between Fbln1 and versican;and 3) Define the role of Fbln1 in controlling NCC proliferation and guidance. Findings from this experimentation are expected to lead to new insights into the mechanism by which Fbln1 guides the normal development of the cardiac OFT, great vessels, cranium and pharyngeal glands and to contribute to an understanding of the etiology of congenital defects involving these tissues. Public Health Relevance: This research seeks to gain a mechanistic understanding of the developmental anomalies (including heart defects) associated with DiGeorge syndrome (DGS), which occurs with a frequency of one in 4000 human births. The proposed studies are designed to determine the role of the extracellular matrix protein, fibulin-1, in regulating the behaviors of cells (neural crest cells) that contribute to the formation of tissues affected in DGS. A novel direction for the research stems from our discovery that fibulin-1 regulates the activity of Fgf8, a growth factor implicated as a key component of the pathway that is dysfunctional in DGS.

Public Health Relevance

This research seeks to gain a mechanistic understanding of the developmental anomalies (including heart defects) associated with DiGeorge syndrome (DGS), which occurs with a frequency of one in 4000 human births. The proposed studies are designed to determine the role of the extracellular matrix protein, fibulin-1, in regulating the behaviors of cells (neural crest cells) that contribute to the formation of tissues affected in DGS. A novel direction for the research stems from our discovery that fibulin-1 regulates the activity of Fgf8, a growth factor implicated as a key component of the pathway that is dysfunctional in DGS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095067-04
Application #
8197683
Study Section
Intercellular Interactions (ICI)
Program Officer
Schramm, Charlene A
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$365,063
Indirect Cost
$117,563
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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