# CNS Fibroblast Formation and Function

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $386,994

## Abstract

Project summary
 The meninges, located between the calvaria bones and brain, are composed of three layers; the pia, arach-
noid, dura. Each meningeal layer contains specialized fibroblasts with unique expression profiles that facilitate
specific functions. The meninges contain resident macrophages called BAMs (border associated macrophages),
directly interact with bones of the skull, and contain extensive blood and lymphatic networks. The adult meninges
provide physical protection, act as a selective barrier, function in neuro-immune surveillance, regulate cerebro-
spinal fluid make-up, and are a site of CNS waste removal. During fetal development, meningeal fibroblasts are
a key paracrine signaling source that regulates neurogenesis and cerebrovascular development via production
of paracrine factors. Primary defects in meningeal fibroblasts cause congenital brain abnormalities in mice and
humans. We have incomplete knowledge of the cellular and molecular mechanisms that control development of
the meninges and its functions in fetal life. Our goal is to fill knowledge gaps on meninges formation and function
and advance knowledge on how primary meninges defects may contribute to neurodevelopmental disorders.
 The transcription factor Foxc1 is required for meninges development and global Foxc1 mutants have been
used for key discoveries of prenatal meningeal fibroblast function. To identify the cell-autonomous role of Foxc1
in fibroblast development and study meningeal fibroblast regulation of calvarial bone and local immune cell de-
velopment, we generated conditional Foxc1 mouse mutants using Tbx18-CreERT that deletes Foxc1 expression
in meningeal fibroblasts and mural cells but not other Foxc1-expressing cells like osteogenic cells. Dorsal fore-
brain meningeal fibroblasts fail to specify into layer-specific subtypes in fetal Foxc1 conditional mutants, instead
differentiating into an abnormal, myofibroblast-like cells. As a result of these primary defects in fibroblast devel-
opment, we show resident meningeal macrophages (BAMs) do not develop properly and prenatal mutant mice
have a severe calvarial bone growth defect. Aim 1 will identify how meningeal fibroblasts regulate BAM devel-
opment, testing the function of meningeal-derived colony stimulating factor-1, and use a maternal infection model
to identify prenatal functions of BAMs and fibroblasts in fetal neuroinflammatory response. Aim 2 will identify
how signals from the meninges control calvarial bone growth over the brain, testing the prediction that meningeal
derived ECM and secreted factors stimulate osteoblast cell migration. Aim 3 will employ single cell Multiome
profiling and transcription factor-DNA binding analysis of Foxc1 and Foxc2 to identify the transcriptional mecha-
nisms that drive meningeal fibroblasts to gain layer specific identities and the ability to produce paracrine factors
that regulate brain, immune, vascular and bone development. Completion of experiments here will...

## Key facts

- **NIH application ID:** 10898356
- **Project number:** 1R01NS131823-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Julie Siegenthaler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,994
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898356

## Citation

> US National Institutes of Health, RePORTER application 10898356, CNS Fibroblast Formation and Function (1R01NS131823-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10898356. Licensed CC0.

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