# Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $465,353

## Abstract

PROJECT SUMMARY
Nell-1 has been studied extensively for its osteogenic role in craniofacial skeletal development. However, despite
its high expression in the brain, there has been a lack of understanding of Nell-1's function in the nervous system
until the recent identification of a ligand-receptor like interaction between Nell-1 and Cntnap4. Cntnap4 is a pre-
synaptic membrane protein whereby global Cntnap4 loss differentially inhibits GABAergic output and augments
dopaminergic transmission, and can induce autism spectrum disorder (ASD)-like behaviors in mice. Remarkably,
ENU-induced Nell-1 haploinsufficient mice exhibit ASD-like behaviors similar to those seen in Cntnap4 mutant
mice. Meanwhile, inactivation of either Cntnap4 or Nell-1 in cranial neural crest cells (CNCCs) gives rise to
remarkably similar calvarial bone defects. Moreover, novel co-localization studies of Nell-1 and Cntnap4 in
mouse and human brains revealed broad neural tissue distribution and high levels of co-localized expression.
Consequently, this proposal hypothesizes that Nell-1 has dual roles in the brain and craniofacial bones (CB) via
a novel interaction between Nell-1 and Cntnap4, and that disruption of the Nell-1/Cntnap4 functional axis will not
only induce deficits in CB, but also interfere with neural transmission in the brain. This proposal advances three
specific aims to investigate the Nell-1/Cntnap4 functional axis in the CB and brain using two new floxed mouse
lines, Nell-1fl/fl and Cntnap4fl/fl. AIM 1 will first define the tissue distribution and expression of Nell-1 and Cntnap4
in both the CB and brain during normal development and growth in wild type (WT) mice. AIM 1 will then specify
the functional contributions of Nell-1 and Cntnap4 to the CB and brain using tissue-specific knockout (KO) Nell-
1Wnt1KO and Cntnap4Wnt1KO mice targeting CNCCs-derived CB and trigeminal ganglions (TG) by Wnt1-Cre, and
Nell-1PV-2AKO and Cntnap4PV-2AKO mice targeting parvalbumin positive (PV+) GABAergic neurons in the brain
and TG by PV-2A-Cre. The CB growth and behavioral changes in these KO mice will be correlated with
morphological changes in the examined bones, brain, and the craniofacial neuroskeletal interface where TG
sensory fibers innervate the CB. AIM 2 will decipher Nell-1's osteogenic property in the context of Cntnap4 during
the repair and regeneration of CB defects in Cntnap4Wnt1KO mice using Nell-1 protein. With Nell-1 serving as an
agonist of Wnt/β-catenin signaling, AIM 2 will determine how integrin β1, a Nell-1 binding partner, and glycogen
synthase kinase-3β (GSK3β), a crucial regulator of β-catenin phosphorylation, modulate Nell-1/Cntnap4
interaction-mediated Wnt/β-catenin signaling activation during CNCC osteogenesis. AIM 3 will investigate Nell-
1/Cntnap4 interaction on brain GABAergic transmission and ASD-like behaviors in Nell-1PV-2AKO and Cntnap4PV-
2AKO mice. AIM 3 will further assess Wnt/β-catenin signaling in the context of Nell-1/Cntnap4 interaction-
...

## Key facts

- **NIH application ID:** 10450876
- **Project number:** 5R01DE029353-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Chia Soo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $465,353
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450876

## Citation

> US National Institutes of Health, RePORTER application 10450876, Dual roles of Nell-1 in craniofacial bones and brain through interaction with Cntnap4 (5R01DE029353-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450876. Licensed CC0.

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