# Investigating novel gene regulatory networks for development of myeloid cells

> **NIH NIH F99** · UNIVERSITY OF NOTRE DAME · 2024 · $49,974

## Abstract

ABSTRACT
Myeloid cells in and around the brain are at the center of proper central nervous system (CNS) function by playing crucial
roles in homeostatic surveillance and immunity1. A type of myeloid cell, microglia, are the resident immune cells of the
CNS and they are vital for neuronal network architecture and injury response1. Conversely, microglia also play a key role
in some diseases like autism2 and multiple sclerosis3. In some cases, microglia depletion is a promising therapy and relies
on known genetic regulators of microglia production4,5. However, recent research in mice and zebrafish shows
subpopulations of developmental microglia that are genetically distinguishable6,7. These data present a gap in knowledge of
the complex gene regulatory networks that govern microglia production. To begin to understand the heterogeneity of
microglia-producing genetic programs, we identified an undescribed cell in the brain that expresses canonical microglia
markers, clears debris, and expands in injury7. These microglia are labeled with Mannose Receptor C, type 1a (mrc1a)7, a
membrane receptor expressed in lymphatic and venous vasculature8. To uncover more about the genetic regulation of these
cells in our supporting data, we interrogated the transcription factor sox17. Sox17 is expressed in endothelium9,10 and was
recently shown to regulate the transdifferentiation of lymphatic vessels to blood vessels11. We found that genetic
perturbation of sox17 significantly reduced mrc1a+ microglia abundance in the embryonic zebrafish brain. Given that sox17
functions in a vast array of embryogenic processes10,12,13, it is difficult to theorize specifically how the transcription factor
could be regulating embryonic microglia production. Therefore, we carried out a CRISPR screen and identified 6 additional
candidate genetic modifiers of microglia production. The aim in the F99 proposed study is to further investigate the
effects of sox17 mutation on microglia and investigate genetic interactions between sox17 and other candidate genetic
modifiers. I will accomplish this by using a combination of in vivo timelapse imaging, in situ hybridization of mRNA, and
CRISPR gene editing. In the K00 phase of the application, the investigation of myeloid cells in and around the brain will
be expanded. Aside from microglia, novel populations of other myeloid cells (monocytes and neutrophils) have also been
identified in the brain14. These monocytes and neutrophils are skull bone-marrow derived, and are genetically distinct from
previously-described populations of these cells14. However, it remains unknown if the skull bone marrow could be a source
for CNS myeloid cells during development and if microglia are amongst these cells. The goal of the K00 proposed study
is to investigate the postnatal skull bone marrow (P7, P10) as a source of myeloid cells during development. I will
accomplish this by using a combination of fate mapping, cell tracking, intravital imaging, and immuno...

## Key facts

- **NIH application ID:** 11001630
- **Project number:** 1F99NS139552-01
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Camden A. Spring
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,974
- **Award type:** 1
- **Project period:** 2024-07-09 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11001630

## Citation

> US National Institutes of Health, RePORTER application 11001630, Investigating novel gene regulatory networks for development of myeloid cells (1F99NS139552-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11001630. Licensed CC0.

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