# THE ROLE OF ADAMTS-A IN REGULATING CNS STRUCTURE AND RESTRICTING CELL MIGRATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $333,594

## Abstract

Abstract: The union of form and function is a core tenet of biology. In animals, tissues often adopt their
characteristic form early in development and maintain it through periods of tremendous growth, a process that
often demands that cells remain largely fixed in place. Tissue shape and cell migration is dictated in large part
by the basement membrane, a special type of extracellular matrix that surrounds tissues, bestowing on them
structural support and resiliency. Yet, how tissues adopt and retain their form and how cells remain anchored
in place during growth and development remain key questions in biology.
 The Drosophila larval CNS is an ideal system in which to explore the genetic and molecular mechanisms
that govern tissue structure and anchor cells in place. The CNS is fully enwrapped by a thick basement
membrane that provides structural support to the CNS via its physical properties and interactions with
underlying surface glia; the CNS grows rapidly during larval stages, maintaining its form despite tremendous
growth, and during this time, neural lineages remain largely fixed in place. The CNS basement membrane
must then maintain its structure and that of the CNS while continually remodeling itself and its interactions
with glia to allow for its growth and that of the CNS. The genetic and molecular principles that bestow upon
the CNS basement membrane, and likely most basement membranes, this power remain cloudy – their
elucidation represents the focus of this proposal.
 We identify AdamTS-A, an extra-cellular metalloprotease, as a key organizer of CNS structure. Reduction in
AdamTS-A function disrupts CNS structure and induces a mass exodus of neurons and cortex glia out of the
CNS. Our studies indicate that AdamTS-A acts in surface glia, the outermost cell layer of the CNS that directly
underlies the CNS basement membrane, to maintain CNS structure and to anchor the underlying neural cells
in place by opposing the actions of collagen IV and integrin, which promote tissue stiffness. Increased tissue
stiffness has been shown to promote cell migration. Thus, we hypothesize that reduction of AdamTS-A function
in surface glia increases the stiffness of the overlying CNS basement membrane, which in a cell non-
autonomous manner then triggers hundreds of CNS neurons and cortex glia to tunnel through the nerves that
project from the CNS toward peripheral tissues fully enwrapped the entire time by the membranes of surface
glia. In this grant, we leverage the strengths of the fly system to clarify the underlying genetic and molecular
mechanisms through which AdamTS-A maintains tissue structure and keeps cells rooted in place in the CNS.
Our specific aims are – (i) to complete a systematic phenotypic characterization of AdamTS-A in the CNS, (ii)
to identify the substrates and interacting proteins of AdamTS-A in the CNS, and (iii) to uncover the genes and
pathways activated in the migrating cells in response to reduced AdamTS-A function in surf...

## Key facts

- **NIH application ID:** 10152383
- **Project number:** 5R01NS036570-23
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** James Benjamin Skeath
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,594
- **Award type:** 5
- **Project period:** 1997-07-28 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152383

## Citation

> US National Institutes of Health, RePORTER application 10152383, THE ROLE OF ADAMTS-A IN REGULATING CNS STRUCTURE AND RESTRICTING CELL MIGRATION (5R01NS036570-23). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10152383. Licensed CC0.

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