The size of tissue layers is scaled during the development of organs. In the nervous system, the size of neurons and glia must be coordinated, particularly for glia such as Schwann cells and satellite cells that are in tight association with axons or neuronal cell bodies. Inappropriate growth of Schwann cells and satellite glia cells in response to nerve damage is linked to chronic pain. Despite its importance, little is understood about how neuronal and glial growth are coordinated. In Drosophila, at least two types of glia increase cell size by increasing DNA content (ploidy), a universal strategy to produce large cells throughout the plant and animal kingdoms. The ability to monitor glial cell size by measuring ploidy and to alter glial cell growth by changing ploidy provides additional experimental advantages to the powerful toolkit in Drosophila for analysis of development of the nervous system. We propose to exploit glial growth by ploidy in the Drosophila nervous system to define mechanisms that coordinate growth between glia and neurons in development. We will investigate one type of surface glia, the subperineurial glia (SPG), that provide the blood-brain barrier. SPG grow to accommodate the underlying neuronal mass while retaining an intact envelope for the blood-brain barrier by increasing ploidy rather than dividing. SPG ploidy is controlled by neuronal mass. The wrapping glia (WG) ensheath axons in the peripheral nervous system. They increase up to 50 fold in size without dividing, apparently by increasing ploidy. We will define the role and regulation of polyploidization of WG.
Our specific aims test three hypotheses: 1) neuronal mass promotes ploidy and size increases for the SPG by increased neuronal activity and/or mechanical tension; 2) increased ploidy of the WG is necessary for growth to permit ensheathment of elongating axons; and 3) the size of the three glial layers in the peripheral nerves is coordinated. Additionally, we will define the transcriptomes of the SPG and WG under normal conditions and when growth is modified by adjacent tissue layers, as a means to identify genes that specify functions of these glia and alter ploidy in response to cues from other cells. The goals of this proposal will be achieved by using Drosophila genetic tools to label cells, inhibit gene activity, or overexpress genes with exquisite developmental specificity.

Public Health Relevance

The two predominant cell types in the nervous system are the neurons and the glia support cells. As the nervous system develops, the growth of neurons and glia must be coordinated for proper function to avoid chronic pain or formation of tumors. Using Drosophila as a model, we will define the mechanisms coordinating growth of glia with neuronal mass and growth between distinct types of glia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092798-03
Application #
9272447
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142