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Molecular Mechanisms of Neuron Motility and Axon Guidance

Award Number: R01NS069913
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2011
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Molecular Mechanisms of Neuron Motility and Axon Guidance - The brain relies for its function on a precise and complex pattern of neuronal connections. The broad long-term goal of this project is to understand molecular mechanisms that set up this pattern of connections during development, and how aberrations of these mechanisms lead to Alzheimer’s Disease (AD) later in life. This project focuses particularly on RNA-based regulatory mechanisms. Key advantages of regulating mRNA translation via RNA-binding proteins (RBPs) are: (1) allowing protein synthesis to be locally regulated in specific subcellular regions where the proteins are needed, and (2) coordinately regulating expression of large networks of functionally related mRNAs. To understand the basic principles of axon guidance, a major model system has been spinal commissural axon guidance at the midline. Navigating this intermediate target requires axons to be attracted and then repelled, and the classic mechanism for this is the ‘Robo switch’ where repellent Robo receptors are upregulated in post-crossing axons; however, the extracellular signal and the mechanism by which it triggers this switch have remained unknown. We have now identified a highly novel mechanism for the Robo switch, involving extracellular ligand binding to the transmembrane Amyloid Precursor Protein (APP), which interacts intracellularly with the RBP CPEB4, to regulate Robo local translation in post-crossing axon segments. Having identified this novel APP-CPEB4 pathway, the proposed studies are designed to expand our understanding of the pathway’s molecular mechanisms and functions. In commissural axon guidance, expression of many proteins is known to be locally regulated in axon segments at the midline; the proposed studies of the APP-CPEB4 pathway are expected to identify coordinate regulation of a large gene network, bringing together many disparate past observations into a unifying model for this premier paradigm of axon guidance. In addition to axon guidance, preliminary studies reveal an overlapping yet distinct set of functions for the same molecular pathway in another major developmental model system, cortical neuron migration. The novel APP-CPEB4 pathway also has high relevance to disease: in addition to its involvement in developmental processes that lead to Autism Spectrum Disorder (ASD), the pivotal role of APP in our pathway gives it key relevance to AD. Regarding autism, abnormalities at the cortical neuron migration stage are believed to be a leading cause of ASD, and CPEB4 disruption in mouse cortex at this specific stage causes ASD-like behaviors. Moreover, all the components of our pathway from ligands to downstream targets have been implicated in ASD, though not previously linked in a unifying model. Regarding AD, the transmembrane structure of APP has long led to the idea that it is a cell surface receptor, yet despite decades of intensive work no instructive receptor role – where the spatiotemporal pattern of a ligand regulates a downstream developmental or physiological function – has yet been identified for APP. Now identifying a receptor role for APP – including a pathway from ligands through a signaling pathway to functional readouts – opens the door to a qualitatively new level of understanding APP, which is especially important since the challenges of therapeutically targeting Aβ place increased emphasis on understanding the roles of APP itself. Studies of our APP-CPEB4 pathway will uncover novel biological principles, while leading to enhanced understanding of mechanisms underlying neurodevelopmental and neurodegenerative disorders. Approaches include genome-wide target mRNA identification, and functional cellular and developmental studies in vitro and in vivo. Additionally, studies of signal transduction mechanisms in the novel APP-CPEB4 pathway will be essential to understand its operation and its potential for therapeutic intervention.


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 = $555,129 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	4/28/2026	EXTENSION WITH OR WITHOUT FUNDS	$555,129
														Subtotal = $555,129

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	10/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $383,585 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/30/2020	NON-COMPETING CONTINUATION	$383,585
														Subtotal = $383,585

Issue Date FY: 2019 ( Subtotal = $383,585 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/1/2019	NON-COMPETING CONTINUATION	$383,585
														Subtotal = $383,585

Issue Date FY: 2018 ( Subtotal = $383,585 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/27/2018	NON-COMPETING CONTINUATION	$38,358
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/12/2018	NON-COMPETING CONTINUATION	$345,227
														Subtotal = $383,585

Issue Date FY: 2017 ( Subtotal = $383,585 )
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	4/1/2017	NON-COMPETING CONTINUATION	$345,227
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	6/9/2017	NON-COMPETING CONTINUATION	$38,358
2017	2015	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/28/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $383,585

Issue Date FY: 2016 ( Subtotal = $383,585 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/23/2016	COMPETING CONTINUATION	$383,585
														Subtotal = $383,585

Issue Date FY: 2015 ( Subtotal = $402,451 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/25/2015	NON-COMPETING CONTINUATION	$402,451
														Subtotal = $402,451

Issue Date FY: 2014 ( Subtotal = $398,423 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/18/2014	NON-COMPETING CONTINUATION	$398,423
														Subtotal = $398,423

Issue Date FY: 2013 ( Subtotal = $387,220 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/5/2013	NON-COMPETING CONTINUATION	$387,220
														Subtotal = $387,220

Issue Date FY: 2012 ( Subtotal = $402,449 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/28/2012	NON-COMPETING CONTINUATION	$402,449
														Subtotal = $402,449

Issue Date FY: 2011 ( Subtotal = $422,542 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/28/2011	NEW	$422,542
														Subtotal = $422,542

Grand Total All Awards = $4,486,139

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Molecular Mechanisms of Neuron Motility and Axon Guidance

Award Number: R01NS069913

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2011

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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