# Evolutionary Conserved Mechanisms of Neuronal Degeneration and Regeneration

> **NIH NIH R21** · STANFORD UNIVERSITY · 2020 · $433,675

## Abstract

Project Summary
Gradual loss of brain function and neurodegeneration are common features of aging throughout diverse phyla.
Understanding how the central nervous system (CNS) regenerates neurons throughout its life is a major area of
interest in regenerative medicine. The study of neural stem cells (NSC) and CNS development and biology has
been an active field of research, however, our knowledge of the precise developmental programs that regulate
NSC dynamics during aging is limited due to the rarity of long term NSCs, the difficulty of monitoring NSCs in-
vivo, and the incredible complexity of mouse and human brains. In this proposal we seek to understand basic
principles and evolutionary conserved elements of neuronal regeneration, degeneration and aging using
Botryllus schlosseri, a primitive chordate with a simple CNS that exhibits assayable and frequent (weekly) CNS
tissue regeneration and degeneration throughout adult life, that can be monitored in vivo thanks to its nearly
transparent body. These organisms can reproduce either sexually through gametes, or asexually through a stem
cell mediated budding process. As a new generation of buds develop into mature individuals (zooids) the bodies
of the old zooids undergo a synchronized wave of programmed cell death. During this weekly regeneration and
degeneration cycle new brains form within the young buds in concert with the destruction of the old zooids’ brain
(Fig 1). This model system offers a unique opportunity to study the cellular and molecular mechanisms that direct
weekly cycles of CNS generation and degeneration in young and old colonies (e.g. <3 months vs. >9 years) and
to identify mutations that accumulate in the DNA of its CNS, stem cells that persist throughout its life. The
Botryllus genome encodes hundreds of brain-associated genes with mammalian homologs. We have undertaken
a systematic molecular (transcriptomic), cellular (FACS) morphological and behavioral characterization of old
and young colonies (Fig 2). Botryllus transcriptome analyses revealed 393 genes that correlate with Alzheimer’s
disease are differentially expressed between young and old colonies (Fig 2C-D). Blood analysis showed an
increased frequency of phagocytic cells in old Botryllus colonies (Fig 2A-B), analogous to the age-associated
shift in mouse and human HSC to favor myeloid cells. Morphological and functional analysis found that the brains
of old colonies are smaller, contain a lower number of cells and have reduced response to stimuli (Fig 2E-F).
Since stem cells are the only cells that self-renew and are maintained throughout the colony’s life, we
hypothesize that genetic mutations that accumulate over time in NSC are the main cause of age associated
neurodegenerative diseases. To test this hypothesis, we plan to characterize the molecular and cellular diversity
of the Botryllus brain in young and old colonies, isolate its NSCs, identify mutations that accumulate in NSC and
progenitor cells DNA, and tes...

## Key facts

- **NIH application ID:** 9979601
- **Project number:** 1R21AG062948-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** IRVING L. WEISSMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,675
- **Award type:** 1
- **Project period:** 2020-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979601

## Citation

> US National Institutes of Health, RePORTER application 9979601, Evolutionary Conserved Mechanisms of Neuronal Degeneration and Regeneration (1R21AG062948-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979601. Licensed CC0.

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