# The Role of GPR161 in the Etiology of Neural Tube Defects

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $390,704

## Abstract

ABSTRACT
Neural tube defects (NTDs) are the second most common human structural birth defect. They result from the
failure of neural tube closure (NTC) during neurulation. There are multiple developmentally-related signaling
pathways involved as NTC processes spatially and temporally. The causes of NTDs are known to be multi-
factorial, including genetic and environmental factors. Given that the genetic factors contribute significantly to
the etiology of NTDs, the identification of specific gene variants and the characterization of their underlying
molecular and cellular mechanisms leading to the etiology of NTDs has progressed slowly over the last several
decades. We have identified novel rare variants of GPR161 using whole genome sequencing (WGS) from large
human cohorts. GPR161 is a known negative regulator of the Shh signaling pathway, and Shh null mice express
NTD phenotypes. The GPR161vl and null mice models suggest the involvement of other signaling pathways. The
Shh, Wnt and PCP signaling pathways are involved in the neural tube patterning, neural stem cell proliferation,
and neural crest cell migration via cell polarization during NTC. We will test the following specific hypothesis with
in vitro and in vivo models. (1) GPR161 can regulate Wnt and PCP signaling pathways, and the novel rare gene
variants of GPR161 adversely impact these signaling pathways, which dysregulate NTC. (2) GPR161 can impact
cell proliferation and cell polarity via Wnt and PCP signaling, respectively, thus the NTD variants of GPR161 will
increase NTD susceptibility by compromising these processes. (3) The identified human GPR161 NTD variants,
alone or in combination with other PCP genes, will produce NTD phenotypes in knock in (KI) mouse models.
The proposed research program will provide the novel molecular, cellular, developmental and genetic links
between GPR161, Wnt and PCP signaling pathways, as they relate to morphogenetic processes involved in
normal NTC. Filling this large datagap can lead us to novel therapeutic strategies for both intervention and
treatment.

## Key facts

- **NIH application ID:** 9936197
- **Project number:** 5R01HD093758-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** RICHARD H. FINNELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,704
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936197

## Citation

> US National Institutes of Health, RePORTER application 9936197, The Role of GPR161 in the Etiology of Neural Tube Defects (5R01HD093758-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9936197. Licensed CC0.

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