# Kinetochore Protein Functions in Synaptogenesis

> **NIH NIH R37** · BOSTON CHILDREN'S HOSPITAL · 2022 · $563,133

## Abstract

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.

## Key facts

- **NIH application ID:** 10475771
- **Project number:** 5R37NS109211-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Thomas L. Schwarz
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,133
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475771

## Citation

> US National Institutes of Health, RePORTER application 10475771, Kinetochore Protein Functions in Synaptogenesis (5R37NS109211-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475771. Licensed CC0.

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