# Functions of Non-erythroid Hemoglobin at the Maternal:Fetal Interface

> **NIH NIH R21** · WASHINGTON STATE UNIVERSITY · 2020 · $191,250

## Abstract

Project Summary/Abstract
Non-erythroid hemoglobin production was first reported in macrophages almost 20 years ago. Since that time,
hemoglobin has been found broadly expressed in a number of tissues under physiological and
pathophysiological conditions including the endometrium and ovary. Surprisingly, very little is known about non-
erythroid hemoglobin production both in terms of its transcriptional regulation and its functions. Some of the
proposed functions for non-erythroid hemoglobin include: 1) oxygen transport/sequestration; 2) regulation of
nitric oxide production/signaling; 3) reducing nitrosative stress; 4) iron transport; 5) antimicrobial actions; and 6)
sequestration of reactive oxygen species (ROS, antioxidant properties). It is interesting to note that a functional
placenta does not exist in the human until several weeks into the first trimester. In mice, the placenta develops
and becomes functional around day 10 of pregnancy, which is half way through gestation. Mechanisms
governing ROS and oxygen bioavailability at the pregnancy interface, particularly pre-placentation, are ill-
defined. In erythroid tissue, hemoglobin and associated genes are regulated by a transcriptional complex that
consists of transcription factor 3 (TCF3), LIM domain binding protein 1 (LDB1), GATA transcription factor 1
(GATA1), and Krueppel-like factor 1 (KLF1). Through mutagenesis studies in mice, our group recently
established that two components of this TCF3/LDB1/GATA1/KLF1 transcriptional complex are essential for
normal fertility in the female. Indeed, conditional uterine ablation of Tcf3 or Ldb1 results in infertility or severe
subfertility, respectively. Furthermore, hemoglobin-α, hemoglobin-β, the rate limiting enzyme in heme production,
aminolevulinic acid synthase 2 (previously thought to be exclusively restricted to the erythroid lineage), and
several hemoglobin biosynthesis-dependent ribosomal proteins were all shown to be down regulated in Tcf3 and
Ldb1 mutant uteri. Based on these findings, it is proposed that uterine-derived hemoglobin serves to tightly
regulate local oxygen tension and prevent accumulation of ROS that would otherwise compromise normal
embryonic/fetal development. The central hypothesis to be tested is that uterine-derived hemoglobin plays a
fundamental role in the establishment and maintenance of pregnancy in mammals. This hypothesis will be tested
by evaluating the consequences of conditionally ablating hemoglobin genes from the uterus during gestation.
From a basic science standpoint, our studies are significant because they will provide meaningful information
related to the transcriptional regulation and function(s) of non-erythroid hemoglobin that will likely be of broad
interest to many areas of biology. From a clinical perspective, these studies will shed new light on possible ways
to enhance in vitro fertilization outcomes and could be used to help explain idiopathic pregnancy failure,
congenital birth defects, or s...

## Key facts

- **NIH application ID:** 9843600
- **Project number:** 5R21HD097641-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** James K Pru
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843600

## Citation

> US National Institutes of Health, RePORTER application 9843600, Functions of Non-erythroid Hemoglobin at the Maternal:Fetal Interface (5R21HD097641-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9843600. Licensed CC0.

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