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Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4

Award Number: R01DE029353
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4 - PROJECT SUMMARY Nell-1 has been studied extensively for its osteogenic role in craniofacial skeletal development. However, despite its high expression in the brain, there has been a lack of understanding of Nell-1's function in the nervous system until the recent identification of a ligand-receptor like interaction between Nell-1 and Cntnap4. Cntnap4 is a pre- synaptic membrane protein whereby global Cntnap4 loss differentially inhibits GABAergic output and augments dopaminergic transmission, and can induce autism spectrum disorder (ASD)-like behaviors in mice. Remarkably, ENU-induced Nell-1 haploinsufficient mice exhibit ASD-like behaviors similar to those seen in Cntnap4 mutant mice. Meanwhile, inactivation of either Cntnap4 or Nell-1 in cranial neural crest cells (CNCCs) gives rise to remarkably similar calvarial bone defects. Moreover, novel co-localization studies of Nell-1 and Cntnap4 in mouse and human brains revealed broad neural tissue distribution and high levels of co-localized expression. Consequently, this proposal hypothesizes that Nell-1 has dual roles in the brain and craniofacial bones (CB) via a novel interaction between Nell-1 and Cntnap4, and that disruption of the Nell-1/Cntnap4 functional axis will not only induce deficits in CB, but also interfere with neural transmission in the brain. This proposal advances three specific aims to investigate the Nell-1/Cntnap4 functional axis in the CB and brain using two new floxed mouse lines, Nell-1fl/fl and Cntnap4fl/fl. AIM 1 will first define the tissue distribution and expression of Nell-1 and Cntnap4 in both the CB and brain during normal development and growth in wild type (WT) mice. AIM 1 will then specify the functional contributions of Nell-1 and Cntnap4 to the CB and brain using tissue-specific knockout (KO) Nell- 1Wnt1KO and Cntnap4Wnt1KO mice targeting CNCCs-derived CB and trigeminal ganglions (TG) by Wnt1-Cre, and Nell-1PV-2AKO and Cntnap4PV-2AKO mice targeting parvalbumin positive (PV+) GABAergic neurons in the brain and TG by PV-2A-Cre. The CB growth and behavioral changes in these KO mice will be correlated with morphological changes in the examined bones, brain, and the craniofacial neuroskeletal interface where TG sensory fibers innervate the CB. AIM 2 will decipher Nell-1's osteogenic property in the context of Cntnap4 during the repair and regeneration of CB defects in Cntnap4Wnt1KO mice using Nell-1 protein. With Nell-1 serving as an agonist of Wnt/β-catenin signaling, AIM 2 will determine how integrin β1, a Nell-1 binding partner, and glycogen synthase kinase-3β (GSK3β), a crucial regulator of β-catenin phosphorylation, modulate Nell-1/Cntnap4 interaction-mediated Wnt/β-catenin signaling activation during CNCC osteogenesis. AIM 3 will investigate Nell- 1/Cntnap4 interaction on brain GABAergic transmission and ASD-like behaviors in Nell-1PV-2AKO and Cntnap4PV- 2AKO mice. AIM 3 will further assess Wnt/β-catenin signaling in the context of Nell-1/Cntnap4 interaction- mediated GABA release, along with the possible additive or synergistic effects of GSK3β inhibitors with Nell-1 in mouse neuronal cells. IMPACT: The ultimate goal is to reveal how the newly identified Nell-1/Cntnap4 interaction may translate into developing Nell-1 as a novel therapeutic to treat human skeletal and neurological pathologies.


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 = -$141,953 )
2026	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	2/10/2026	NON-COMPETING CONTINUATION	-$141,953
														Subtotal = -$141,953

Issue Date FY: 2024 ( Subtotal = $460,652 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	5	7/26/2024	NON-COMPETING CONTINUATION	$460,652
														Subtotal = $460,652

Issue Date FY: 2023 ( Subtotal = $470,053 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	4	7/21/2023	NON-COMPETING CONTINUATION	$470,053
														Subtotal = $470,053

Issue Date FY: 2022 ( Subtotal = $465,353 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	3	7/29/2022	NON-COMPETING CONTINUATION	$465,353
														Subtotal = $465,353

Issue Date FY: 2021 ( Subtotal = $540,940 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	2	7/14/2021	NON-COMPETING CONTINUATION	$540,940
														Subtotal = $540,940

Issue Date FY: 2020 ( Subtotal = $562,927 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	001	1	9/4/2020	SUPPLEMENT FOR EXPANSION	$69,004
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Oral Diseases and Disorders Research	000	1	7/29/2020	NEW	$493,923
														Subtotal = $562,927

Grand Total All Awards = $2,357,972

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Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4

Award Number: R01DE029353

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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