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Mechanism of Wnt5a signaling in skeletal development and diseases

Award Number: R01AR081646
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Mechanism of Wnt5a signaling in skeletal development and diseases - The skeletal system provides crucial structural and functional support to the body. The long-term objective of this project is to uncover the pathogenesis of congenital skeletal disorders and develop strategies for skeletal regeneration by elucidating the key signaling mechanisms governing skeletal development. Early mouse genetic studies have uncovered a critical role of Wnt5a in limb skeletal development. Human mutations in WNT5A have also been implicated in Autosomal Dominant Robinow syndrome (ADRS), a disorder that manifests dwarfism and widespread skeletal dysplasia. Studies over the past 20 years have revealed that Wnt5a is a non-canonical Wnt ligand that signals through receptor Frizzled (Fz) and co-receptors Ror1/2 to activate the planar cell polarity (PCP) pathway for limb morphogenesis during skeletal formation. The objective of the current proposal is to characterize several fundamental properties of Wnt5a as a potent morphogen, such as its signaling potency and range, the structural foundation that governs these properties, and how human ADRS mutations alter its structure to modify WNT5A signaling. The objective will be achieved by specifically testing 1) how two Wnt5a isoforms that differ by 18aa residues at the N-terminus may function differently in PCP signaling to impact limb development; 2) how the Wnt5a isoforms and ADRS mutations may alter the mode through which Wnt5a clusters together Fz and Ror to trigger PCP signaling; and 3) how the ADRS mutations alter Wnt5a’s signaling potency and range during early limb development and endochondral bone formation. Building on our preliminary studies that mouse transgenes encoding different Wnt5a isoforms display remarkably different functional range in the limb, and that the two isoforms display different potency in activating PCP in the Xenopus model, we will first determine whether their function range is solely determined by the activity level difference, or additional factors such as dispersal ability during limb development. Secondly, we will use a set of biochemical and biophysical assays to test a structural biology based model, in which different N-terminal residues in Wnt5a isoforms and ADRS variants may alter the mode through which Wnt5a brings together Fz and Ror to form distinct type of ligand/receptor complexes with different activity levels. Thirdly, we will use a set of quantitative functional and molecular readout to determine how the ADRS variants may cause elevated PCP signaling activity in Xenopus, and how these variants impact Wnt5a- mediated skeletal development and endochondral bone formation in the mouse. These studies will elucidate mechanistically how the N-terminal region may regulate Wnt5a’s signaling activity in PCP, and how alterations in the N-terminus leads to skeletal defects in ADRS in humans.


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: 2026 ( Subtotal = $533,408 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	3/6/2026	NON-COMPETING CONTINUATION	$533,408
2026	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/31/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $533,408

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $605,371 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/9/2024	NON-COMPETING CONTINUATION	$605,371
														Subtotal = $605,371

Issue Date FY: 2023 ( Subtotal = $624,147 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/27/2023	NON-COMPETING CONTINUATION	$624,147
														Subtotal = $624,147

Issue Date FY: 2022 ( Subtotal = $649,392 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/12/2022	NEW	$649,392
														Subtotal = $649,392

Grand Total All Awards = $2,412,318

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Mechanism of Wnt5a signaling in skeletal development and diseases

Award Number: R01AR081646

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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