# Molecular signaling in uterine receptivity to implantation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $439,064

## Abstract

Embryo implantation is a gateway to pregnancy success. A crosstalk between the blastocyst and
uterus is vital to implantation. Formation of a healthy implantation chamber (crypt) is critical for
normal embryo implantation; an abnormal crypt results in subfertility. Planar cell polarity (PCP) is a
classic downstream target of the non-canonical Wnt5a signaling pathway. Uterine deletion of Vang-
like protein 2 (Vangl2), a major PCP component, severely derails crypt formation, embryo spacing,
and decidualization, ultimately compromising pregnancy outcomes. We have found that crypts
invariably originate with preexisting glands conferring direct communication between the implanting
blastocyst and glands. Heparin-binding EGF-like growth factor (HB-EGF) is exclusively expressed
in the crypt epithelium surrounding the blastocyst, and beads preloaded with HB-EGF, if transferred
to day 4 pseudopregnant uteri, evoke implantation-like changes similar to normal pregnancy.
However, these responses fail to occur in uteri missing Vangl2, suggesting an intersection of Vangl2
with HB-EGF signaling. HB-EGF executes its function via the EGF family of receptors (Erbbs 1-4)
as homodimers or heterodimers and induces tyrosine phosphorylation. This proposal will test a novel
hypothesis that HB-EGF signaling intersects with PCP signaling by engaging the ErbBs in
implantation. HB-EGF working via ErbBs 1-4 induces tyrosine phosphorylation. Our preliminary
results show a physical association of Vangl2 with ErbB2 and ErbB3, suggesting that these
receptors, if activated by HB-EGF, transphosphorylate Vangl2. The following two specific aims will
study interactions between PCP and HB-EGF signaling in implantation using mouse models:
Specific aim 1 will test the hypothesis that HB-EGF signaling intersects with Vangl2 signaling to direct
the formation of an appropriate glands-crypt assembly for direct cross-talk between the implanting
blastocyst and the glands. This interlocking of two different signaling pathways involves
phosphorylation of members of the ErbB family of receptors followed by transphosphorylation of
Vangl2. Specific aim 2 will test the hypothesis that the functional coupling of HB-EGF and Vangl2
signaling in implantation requires the presence of ErbB1, ErbB2 and/or ErbB3 in the uterine epithelium
and/or stroma. We will use conditional deletion of ErbB1, ErbB2 and/or ErbB3 using Pgr-Cre and Ltf-
iCre drivers to explore the Vangl2 phosphorylation status in the uterus, and correlate these results with
pregnancy phenotypes. Successful completion of this project will reveal a conceptual attribute to the
field of implantation and pregnancy biology that a growth factor signaling pathway intersects with PCP
signaling in forming implantation chambers (crypts) for pregnancy success.

## Key facts

- **NIH application ID:** 10434387
- **Project number:** 2R01HD068524-11
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Sudhansu K Dey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $439,064
- **Award type:** 2
- **Project period:** 2011-09-26 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434387

## Citation

> US National Institutes of Health, RePORTER application 10434387, Molecular signaling in uterine receptivity to implantation (2R01HD068524-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434387. Licensed CC0.

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