# Examining the Function of Biological Sex Specific Genes: the NLGN4s

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $343,681

## Abstract

Abstract
NLGNs are known to play crucial roles in synaptogenesis and the maturation of the postsynaptic density
through recruitment of and interactions with scaffolding proteins, neurotransmitter receptors, and ion
channels. It has been shown that NRXN binding is crucial for NLGN function, as NRXN is capable of
clustering NLGNs at the postsynaptic density (PSD) and initiating recruitment of downstream interacting
proteins necessary for synapse stabilization and maturation. Most vertebrates possess four NLGN genes:
NLGN1, NLGN2, NLGN3, and NLGN4. In most mammals, NLGN4 is located on the X chromosome,
however in higher order primates such as Homo sapiens and Pan troglodytes NLGN4X is complemented
on the Y chromosome (sometimes referred to as NLGN5) with nearly 98% homology to NLGN4X. It is
believed that this NLGN4Y isoform originated from a duplication event that occurred relatively recently
during evolution Unlike almost all vertebrates, humans possess X chromosome and Y chromosome
isoforms of NLGN4, however the function of NLGN4 at synapses remains unknown. We intend to
investigate the functional properties of NLGN4X and NLGN4Y such as NRXN binding, synaptogenesis,
and localization.
We plan on addressing these questions with the following three specific aims: 1) Determine
whether NLGN4X and NLGN4Y are localized to human synaptic sites. 2) Determine the affinities of
NLGN4X and NLGN4Y for NRXN. 3) Determine the molecular mechanism responsible for
differences in the synaptogenic activity of NLGN4X and NLGN4Y. We have conducted experiments to
demonstrate that we can achieve the goals of each of the three ambitious aims we proposed. For specific
aim 1, we established approaches to study NLGN function in human brain tissue and cells. For Specific
aim 2, we have established an assay and begun experiments to determine the affinity of NLGN4 in
biological sex-specific combinations. For specific aim 3, we have begun experiments using a synapse
assay system and expressed NLGN4X and NLGN4Y and generated constructs to begin structure function
analysis. Together these preliminary data indicate that we are poised to make rapid progress on our
understanding of these sexually dimorphic genes. Results are likely to shed light on the matter of synaptic
dysfunction in disorders such as ASD and learning disabilities and propose a potential difference in
synaptic function between males and females.

## Key facts

- **NIH application ID:** 10938403
- **Project number:** 7R01NS106906-06
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Matthew B Dalva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $343,681
- **Award type:** 7
- **Project period:** 2018-05-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938403

## Citation

> US National Institutes of Health, RePORTER application 10938403, Examining the Function of Biological Sex Specific Genes: the NLGN4s (7R01NS106906-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10938403. Licensed CC0.

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