# Novel Developmental Regulation of Bmp and nodal signaling by Tril

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $310,109

## Abstract

Our long term goal is to understand how Bmp and Tgf-ß/nodal signaling is regulated in development and disease.
Imbalances in Bmp and Tgf-ß/nodal signaling lead to birth defects and cancers, and yet knowledge of how the
equilibrium between these pathways is maintained is incomplete. We identified Tril as a protein that coordinately
regulates Bmp and nodal signaling and propose that it does so through a novel mechanism involving Toll-like
receptors (Tlrs). Tlrs play evolutionarily conserved roles in mediating innate immune responses. The proposed
studies will provide the first demonstration that Tlr signaling is also required for early patterning in vertebrates,
and will set the stage for future studies that ask whether Tril or downstream signaling components play a
protective and/or causal role in congenital anomalies and disease. Our published studies show that Tril triggers
degradation of Smad7 to enhance Bmp signaling during gastrulation in Xenopus, and our new data show that
Tril simultaneously inhibits nodal signaling. Our data support the hypothesis that Tril serves as a co-receptor for
Tlrs to initiate a signaling cascade in which Irak kinases activate Pellino2. Pellino2 then stimulates Rnf12-
mediated degradation of Smad7 to enhance Bmp signaling, and Nedd4L-mediated degradation of nodal
signaling components to inhibit nodal signaling. We will test this hypothesis as follows (1) Determine how Tril
regulates Nedd4l to inhibit nodal signaling. We will compare the kinetics of nodal pathway inactivation, analyze
steady state levels of nodal receptors and ask whether Nedd4l is sufficient to rescue nodal signaling in control
and Tril deficient Xenopus embryos and mouse embryonic fibroblasts (MEFs). We will test whether Tril prevents
proteosomal degradation and/or stimulates post-translational modification of Nedd4l. (2) Determine whether and
how Tril regulates Rnf12 to mediate degradation of Smad7. We will test whether the ability of Tril to trigger
degradation of Smad7 is impaired in embryos or in MEFs in which expression of Rnf12 is knocked down, and
conversely, whether Rnf12-mediated degradation of Smad7 is impaired in Tril morphants and in tril mutant MEFs.
We will test whether steady state levels, subcellular localization and/or post-translational modification of Rnf1 is
altered in Tril morphant embryos and tril mutant MEFs. (3) Determine whether Tril activates a Tlr-signaling
cascade to regulate Bmp and nodal signaling. We will down-regulate the function of Tlr3, Tlr4, Iraks and Pellino2
in embryos and in MEFs and ask whether Bmp signaling is impaired and nodal signaling is enhanced, and we
will upregulate the function of each protein and ask whether this rescues Bmp and nodal signaling in Tril
morphant embryos and tril mutant MEFs. We will test whether Tril is required to regulate Pellino2
phosphorylation, subcellular localization and/or binding to Smad7 and Nedd4l, and will use rescue assays to
determine if phosphorylation of Pellino2 an...

## Key facts

- **NIH application ID:** 10151464
- **Project number:** 5R01HD067473-09
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jan L Christian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $310,109
- **Award type:** 5
- **Project period:** 2012-02-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151464

## Citation

> US National Institutes of Health, RePORTER application 10151464, Novel Developmental Regulation of Bmp and nodal signaling by Tril (5R01HD067473-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10151464. Licensed CC0.

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