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Role of autism-linked genes in developmental refinement of the corpus callosum

Award Number: R01MH111674
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Role of autism-linked genes in developmental refinement of the corpus callosum - The corpus callosum (CC) provides interhemispheric communication essential for cognitive and associative processes, with critical roles in several higher order functions including sensory processing, motor coordination, and language acquisition and formation. Malformation of the CC has devastating functional consequences; agenesis and hypoplasia of the CC is linked to several conditions associated with severe neurological and cognitive disabilities. In addition, anatomical and physiological deficits of the CC also have been commonly reported in several neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). Yet, the cellular and molecular mechanisms involved with the malformation of the CC in these disorders remain undefined. Our current understanding of CC development is exclusively limited to factors and mechanisms involved with the early axon guidance phase, as well as those involved with the later myelination and synaptogenesis stages. However, the regulation of early postnatal CC refinement, in which initially produced callosal axons are selectively preserved or eliminated, remains completely unknown and is vastly understudied. Our major goal is to elucidate the mechanisms underlying the critical but vastly unexplored early postnatal processes governing CC development. This understanding will be crucial in shedding light on the pathogenesis of callosal abnormalities in neurodevelopmental disorders. Along with axon elimination, axon preservation is critical in maintaining the appropriate neuronal connections during this developmental refinement period, which leaves a lasting impact throughout the life of the organism. Our preliminary investigation has led to us to an intriguing hypothesis that the autism-linked gene, Plexin-A4, selectively preserves a subset of callosal axons during early postnatal CC refinement via the inhibition of caspase-mediated tubulin cleavage. In this proposed project, we will first establish the as-of-yet unconfirmed developmental elimination of callosal axons in the mouse CC (Aim 1). We will then test our hypothesis using various genetic and molecular biological techniques through our mouse model of CC refinement (Aim 2). We will then define molecular links between Plexin-A4 and caspase inhibition, a relationship which has previously been unknown, as well as identify novel autism-linked genes that are essential in the postnatal maintenance/elimination of callosal axons, using a unique combination of mass spectrometry and single-cell RNA sequencing (Aim 3). These results will, for the first time, validate the use of a mouse model to study the fundamental process of axon preservation during the postnatal refinement of the CC, and identify molecular pathways critical for this process. This novel study will also provide avenues for deciphering mechanisms underlying abnormal CC formation implicated in functional deficits associated with ASD and other neurodevelopmental disorders. Our results will open new avenues to therapeutic approaches by targeting these molecular pathways for abnormal CC development.


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	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	5	1/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $437,500 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	5	4/8/2021	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2020 ( Subtotal = $437,500 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	4	4/23/2020	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2019 ( Subtotal = $551,231 )
2019	2019	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	3	4/17/2019	NON-COMPETING CONTINUATION	$551,231
														Subtotal = $551,231

Issue Date FY: 2018 ( Subtotal = $551,231 )
2018	2018	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	2	4/23/2018	NON-COMPETING CONTINUATION	$437,500
2018	2018	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	001	2	4/24/2018	SUPPLEMENT FOR EXPANSION	$113,731
														Subtotal = $551,231

Issue Date FY: 2017 ( Subtotal = $437,500 )
2017	2017	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	1	6/13/2017	NEW	$437,500
														Subtotal = $437,500

Grand Total All Awards = $2,414,962

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Role of autism-linked genes in developmental refinement of the corpus callosum

Award Number: R01MH111674

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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