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Kinetochore Protein Functions in Synaptogenesis

Award Number: R37NS109211
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Kinetochore Protein Functions in Synaptogenesis - Project Summary From a Drosophila mutant screen for defects in the formation of the embryonic neuromuscular junction (NMJ), we have learned that mutations in components of the kinetochore complex are needed for the transformation of a growth cone into a correctly shaped synaptic connection. Loss of these proteins also alters the structure of sensory dendrites. In cultured mammalian neurons, kinetochore proteins also appear to guide development: their knockdown by RNAi causes an excess of filipodia like protrusions to form on hippocampal dendrites. This is a completely novel function for the kinetochore, a protein complex previously known only to function at the centromere of chromosomes where it is required in dividing cells to “catch” and stabilize spindle microtubules and thereby enable the segregation of chromosomes to the daughter cells. The neuronal phenptypes cannot be explained by defects in chromosome mechanics and therefore we hypothesize a postmitotic function for a “neuro-kinetochore”, a function that is likely to involve the same core property of the centromeric kinetochore: the ability to bind to the plus-ends of microtubules and stabilize them. We propose to test the hypothesis that a complex very much akin to that found at centromeres will function locally in post-mitotic neurons to assist in the transformation of dynamic growth cone microtubules into stable bundles of synaptic microtubules and similarly to stabilize dendritic microtubules and thereby arrest dendrite growth. The proposal makes use of the advantages of both Drosophila and mammalian systems. Aim 1 of this proposal therefore seeks to characterize in greater depth the nature of the defects at the embryonic fly NMJ and in hippocampal dendrites. Aim 2 delves into the mechanism underlying the phenotype by asking whether structure function studies support the hypothesis of a kinetochore-like structure that must bind to microtubules. Aim 3 focuses on the microtubule cytoskeleton and asks whether there are defects in microtubule dynamics and stabilization in the mutants, and how this novel role for kinetochore proteins fits into our knowledge of the processes that transform growth cones into mature endings and determine the morphology of dendrites.


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: 2025 ( Subtotal = $619,447 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	8/4/2025	NON-COMPETING CONTINUATION	$619,447
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$3,268
2025	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/18/2025	NON-COMPETING CONTINUATION	-$3,268
														Subtotal = $619,447

Issue Date FY: 2024 ( Subtotal = $600,864 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	8/20/2024	NON-COMPETING CONTINUATION	$600,864
														Subtotal = $600,864

Issue Date FY: 2023 ( Subtotal = $619,447 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/21/2023	EXTENSION WITH OR WITHOUT FUNDS	$619,447
														Subtotal = $619,447

Issue Date FY: 2022 ( Subtotal = $563,133 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	8/19/2022	NON-COMPETING CONTINUATION	$563,133
														Subtotal = $563,133

Issue Date FY: 2021 ( Subtotal = $553,785 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/26/2021	NON-COMPETING CONTINUATION	$553,785
														Subtotal = $553,785

Issue Date FY: 2020 ( Subtotal = $544,705 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/27/2020	NON-COMPETING CONTINUATION	$544,705
														Subtotal = $544,705

Issue Date FY: 2019 ( Subtotal = $551,361 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/12/2019	NEW	$551,361
														Subtotal = $551,361

Grand Total All Awards = $4,052,742

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Kinetochore Protein Functions in Synaptogenesis

Award Number: R37NS109211

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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