# Mechanisms of naturally-occurring astrocyte death during development

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $395,401

## Abstract

ABSTRACT
Naturally-occurring developmental cell death is a fundamental pattern formation mechanism in the nervous
system. Whether and how cell death sculpts the astrocyte population is not known. The objective here is to
gain insight into astrocyte patterning by learning the mechanisms underlying naturally-occurring astrocyte
death in the mouse retina. The central hypothesis is that microglia kill and engulf retinal astrocytes in response
to astrocyte-derived “eat-me” signals, thereby regulating astrocyte numbers and patterning. The rationale for
this work is that retinal astrocytes dictate the pattern of developing vasculature. Knowledge of astrocyte death
mechanisms will make it possible to study novel factors that shape the ultimate pattern of the astrocyte and
vascular networks – in both normal and pathological developmental contexts. To this end, the following Specif-
ic Aims are proposed: 1) Determine cellular mechanisms for developmental cell death of retinal astro-
cytes. Preliminary studies show that retinal astrocytes are initially overproduced and then culled between
postnatal days 5 and 14. These studies further suggest the working hypothesis that microglia are responsible
for killing and eliminating astrocytes during this period. This will be tested in vivo using complementary anatom-
ical and chemogenetic approaches. 2) Identify molecular mechanisms responsible for astrocyte elimina-
tion during development. Preliminary data show that apoptosis cannot account for developmental loss of ret-
inal astrocytes. Instead, a tripartite trans-cellular molecular complex – comprising phosphatidylserine on the
astrocyte surface, the soluble lipid-binding protein MFGE8, and αvβ5 integrins on microglia – is implicated as a
key mediator of astrocyte death. This working hypothesis will be tested using mouse genetic tools in vivo. 3)
Determine contribution of developmental death to astrocyte patterning in a disease model. In both mice
and humans, neonatal hypoxia exposure can perturb formation of retinal vasculature. Because astrocytes
serve as a patterning template for developing vessels, astrocyte patterning defects might contribute to hypoxia-
induced vascular pathology. A novel mouse model was developed to study this issue. Preliminary data from
this model led to the working hypothesis that microglia-mediated astrocyte death is impaired by hypoxia, caus-
ing astrocyte and vessel patterning defects. This will be tested by comparing two mouse strains: a hypoxia-
sensitive strain, and a resilient strain that recovers from initial hypoxia-induced pathology. Completion of these
aims is expected to: 1) provide the first mechanistic understanding of developmental astrocyte death; and 2)
begin to reveal the function of death in patterning the retinal astrocyte population. This contribution will be sig-
nificant because it is expected to illuminate how specific pattern formation mechanisms enable astrocyte func-
tions, in the retina and throughout the ne...

## Key facts

- **NIH application ID:** 10019560
- **Project number:** 5R01EY030611-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Jeremy N Kay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $395,401
- **Award type:** 5
- **Project period:** 2019-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019560

## Citation

> US National Institutes of Health, RePORTER application 10019560, Mechanisms of naturally-occurring astrocyte death during development (5R01EY030611-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10019560. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*