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Understanding how Connexin43 regulates joint formation in the regenerating zebrafish fin

Award Number: R15HD080507
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary Synovial joints are critical for skeletal form and function, but are susceptible to debilitating diseases such as osteoarthritis and injury. While much is known about the composition and mechanics of functioning joints, relatively little is known about how joint-forming cells (JFCs) are specified in a particular location, thereby permitting the development of joints that provide flexibility. Addressing this gap in knowledge could facilitate the development of novel therapies for joint disease by targeting molecular pathways influencing cell fate decisions. The zebrafish regenerating fin is an important model system for addressing fundamental questions of skeletal development, including the specification and commitment of JFCs. The fin skeleton is made of bony fin rays, and each fin ray is made of bony segments separated by joints. Thus, the fin is a rich source of joints, which are produced regularly during typical outgrowth and during regeneration. The osteoblasts and JFCs that build the fin skeleton are derived from a common skeletal precursor cell (SPC) located in the lateral fin ray mesenchyme. Recent studies from the Iovine lab provide strong evidence that Connexin43 (Cx43), via gap junctional intercellular communication (GJIC), influences JFC specification by suppressing expression of evx1. Evx1 is a transcription factor required for joint formation. The overall objectives for this proposal are to reveal the nature of Cx43-GJIC, and to reveal the subsequent mechanism of evx1 suppression. The central hypothesis of this proposal is that Cx43-GJIC influences joint formation by transducing changes in membrane potential to the SPCs; changes in membrane potential in turn trigger changes in gene expression that influence evx1 expression, JFC specification, and joint formation. This hypothesis was formulated on the basis of prior and preliminary data. For example, Cx43-GJIC promotes simplet (smp) expression in SPCs. Smp is required to bring -catenin to the nucleus. In concert with Lef1 or TCF7 transcription factors, -catenin (directly or indirectly) suppresses evx1 transcription. The Aims of this proposal are designed to test the central hypothesis. Aim 1 is to test if changes in membrane resting potential are sufficient to influence gene expression in SPCs. This will be accomplished by driving membrane hyperpolarization or depolarization in Cx43-expressing cells, and evaluating smp and evx1 expression in SPCs. Aim 2 is to identify cis-regulatory elements (CREs) that influence evx1 transcription. Putative CREs will be deleted from a BAC reporter for evx1, and impacts on reporter expression will be assessed to reveal likely enhancers or silencers acting on evx1. Completion of these Aims will significantly advance our understanding of signals mediated by GJIC influencing cell specification, and will further provide novel insights into the spatiotemporal regulation of JFC specification.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	3	7/18/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	001	3	12/10/2021	COMPETING CONTINUATION	$102,510
2022	2018	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	2	12/10/2021	COMPETING CONTINUATION	-$102,510
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $483,000 )
2021	2021	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	001	3	8/31/2021	COMPETING CONTINUATION	$483,000
2021	2018	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	2	8/24/2021	COMPETING CONTINUATION	$0
														Subtotal = $483,000

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	001	2	2/8/2019	COMPETING CONTINUATION	$66,836
2019	2015	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	1	2/8/2019	NEW	-$66,836
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $483,000 )
2018	2018	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	001	2	8/28/2018	COMPETING CONTINUATION	$483,000
2018	2015	LEHIGH UNIVERSITY	526 BRODHEAD AVE	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	1	8/23/2018	NEW	$0
														Subtotal = $483,000

Issue Date FY: 2015 ( Subtotal = $483,000 )
2015	2015	LEHIGH UNIVERSITY	526 BRODHEAD AVENUE,BLDG #23B	BETHLEHEM	PA	18015	NORTHAMPTON	USA	Child Health and Human Development Extramural Research	000	1	8/14/2015	NEW	$483,000
														Subtotal = $483,000

Grand Total All Awards = $1,449,000

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Understanding how Connexin43 regulates joint formation in the regenerating zebrafish fin

Award Number: R15HD080507

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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