# Signaling pathways that regulate scaling and regeneration of the cerebellum

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $506,544

## Abstract

The cerebellum, consisting of 80% of the neurons in the human brain, is involved in balance and motor
coordination, and also modulates language, reasoning and social processes via its forebrain circuits. The
developing cerebellum is particularly sensitive to factors that impact on growth (or cause injury) around birth,
since much of its growth occurs in the third trimester and continues after birth. The postnatal cerebellar cortex
has two proliferating stem/progenitor populations, one dedicated to making excitatory granule cells and the
other to interneurons and astrocytes. Whereas great advances have been made in defining the
stem/progenitor cells and lineages that generate the developing cerebellum, little is known about the ability of
the cerebellum to produce new cells following injury. We recently discovered that the mouse cerebellum has a
large capacity to replenish cells killed around birth. First, we found that Nestin-expressing progenitors (NEPs)
that normally are dedicated to the astrocyte lineage are reprogrammed to become granule cell precursors
(GCPs) when the latter are killed by irradiation or genetic approaches. Furthermore, at least two spatially and
transcriptionally distinct NEP subtypes that are lineage-restricted have different responses to the loss of GCPs
to achieve proper scaling of cell types after injury. Second, Purkinje cells (PCs), which are born by embryonic
day 13.5, are rapidly replaced via proliferation of rare immature Purkinje cells (iPCs) following PC killing, and
replenishment of PCs is age-dependent. Finally, signals released by dying cells, such as reactive oxygen
species (ROS), and cells in the microenvironment can have critical influences on repair responses of
progenitor cells. Preliminary results showed that cells in microenvironment have distinct cellular responses in
each of our injury models. We will address two critical questions for both injuries: i) What are the gene
expression changes that underlie the cellular transitions necessary for cell replenishment and ii) what are the
roles of dying cells, immune cells and glia in regeneration. Our central hypothesis is that cerebellar progenitors
and rare immature neurons maintain distinct transcriptional plasticity and along with cells in the
microenvironment respond differently to killing of GCPs and PCs. Our specific aims are to: 1) Uncover the
transcriptional signatures of NEP subtypes and iPCs during development and regeneration, and identify
pathways required for proliferation and neuron production using single cell and mutant analyses. 2) Determine
how the microenvironment influences NEP and iPC injury responses.

## Key facts

- **NIH application ID:** 10093148
- **Project number:** 5R01NS092096-07
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** ALEXANDRA L. JOYNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $506,544
- **Award type:** 5
- **Project period:** 2015-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093148

## Citation

> US National Institutes of Health, RePORTER application 10093148, Signaling pathways that regulate scaling and regeneration of the cerebellum (5R01NS092096-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10093148. Licensed CC0.

---

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