# Mechanisms of Developmental Spine Pruning Regulated by IgCAMs and Semaphorins

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $388,750

## Abstract

Abstract
Elimination of excess dendritic spines on cortical pyramidal neurons during adolescence is critical for
excitatory/inhibitory (E/I) balance in adult cortical circuits, and its impairment can lead to altered spine density
in autism spectrum disorders (ASD) and schizophrenia. This proposal seeks to illuminate a novel mechanism
for dendritic spine remodeling in the developing mammalian frontal cortex, mediated by immunoglobulin (Ig)-
class cell adhesion molecules of the L1 family and class 3 Semaphorins. Aims focus on NrCAM (Neuron-Glial
Related Cell Adhesion Molecule) and Close Homolog of L1 (CHL1), which are associated with ASD,
schizophrenia, and intellectual disability. The central hypothesis to be investigated is that NrCAM and CHL1
form holoreceptor complexes with Neuropilin1/2 and PlexinAs for secreted class 3 Semaphorins, which signal
through Rho GTPases to prune dendritic spines of cortical pyramidal neurons during adolescence.
Aim 1. Developmental Regulation of NrCAM and Role of CHL1 in Dendritic Spine Remodeling
A new conditional mutant mouse (Nex1Cre-ERT2: NrCAMf/f) that inducibly deletes NrCAM from cortical
pyramidal neurons will be studied to define the developmental timing of NrCAM function in dendritic spine
morphogenesis, spine dynamics, and cortical excitability. A novel function for CHL1 in spine remodeling will be
identified by analysis of spine/synapse morphogenesis and cortical excitability in CHL1 null mutant mice.
Aim 2. Structural and Functional Interactions of the Sema3F Holoreceptor
A structure-function approach using mutagenesis will be undertaken to probe an innovative molecular model of
the Sema3F holoreceptor complex, in which the NrCAM extracellular domain interacts with Npn2 to induce
Sema3F-induced receptor clustering and spine remodeling. NrCAM cytoplasmic domain interactions with
Synapse-associated protein 102 (SAP102) and cytoskeletal adaptors (Ankyrin-B, -G, and Doublecortin-like
kinase 1) will be analyzed for promoting receptor clustering and signaling at the nascent postsynaptic density
in cortical neuronal cultures and in vivo.
Aim 3. Molecular Mechanism of Sema3F Signaling through Small GTPases
A novel dual signaling pathway will be investigated in which Sema3F-induced signaling through RhoA (Rho
Kinase-Myosin II) generates contractile force that exerts tension on actin filaments assembled through Rac1
signaling (Tiam1-Rac1-PAK-LIMK1-Cofilin1) to regulate spine elimination/protrusion. The role of intrinsic
activity in Sema3F-mediated spine pruning will be evaluated by activity blockade in cortical neuron cultures.
 This project is expected to have sustained overall impact as it will delineate a novel molecular
mechanism for regulating excitatory synapse development in the frontal neocortex, advance mechanistic
understanding into pathology associated with neurodevelopmental disorders, and may reveal new therapeutic
targets for intervention in adolescence, a window of opportunity for influencing corti...

## Key facts

- **NIH application ID:** 10101677
- **Project number:** 5R01MH113280-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Patricia F Maness
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10101677

## Citation

> US National Institutes of Health, RePORTER application 10101677, Mechanisms of Developmental Spine Pruning Regulated by IgCAMs and Semaphorins (5R01MH113280-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10101677. Licensed CC0.

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