The cerebellum (CB), consisting of 80% of the neurons in the human brain, not only has a major role in balance and motor coordination, but also modulates language, reasoning and social processes via neural circuits that connect throughout the forebrain. The ratio of the number of neurons in the CB to the cerebral cortex is remarkably constant across mammalian species, indicating that interconnected circuits have scaled together during evolution. Since much of CB growth occurs in the third trimester and continues for a year after birth, the CB is particularly vulnerable to clinical and environmental factors. Granule cell production, stimulated Sonic Hedgehog (Shh) secreted by Purkinje cells, accounts for a majority of cerebellar growth during this period. Pre-term babies are at a significantly higher risk of developing cerebellar hypoplasia and neurological dysfunction, likely in part because they receive glucocorticoids. In rodent models, glucocorticoids increase death of granule cell precursors (GCPs) in the external granule cell layer (EGL), through a mechanism that involves altered SHH-GLI signaling. However, our preliminary results and other experimental models have demonstrated that the developing rodent CB has a large capacity to regenerate a depleted EGL. In order to enhance recovery from a transient insult to the developing CB, it is critical to identify the signaling pathways that stimulate compensatory expansion of cells, and ensure that all cell types scale together in order to have normally functioning circuits. We will utilize sophisticated mouse genetics approaches to identify such pathways. Our studies are based on the unique discovery we made that when the anterior EGL of the CB is depleted at birth, cells marked with Nestin-FlpoER in the white matter expand and populate the EGL and then differentiate, producing a major recovery. Our preliminary studies and novel genetic approaches provide a powerful approach for studying the cellular behaviors of normal and mutant Nestin-expressing white matter stem cells in response to depletion of the EGL and discovering the signals that stimulate expansion of white matter stem cells and their population of the EGL. Our studies should provide insights that can be used to develop new approaches for augmenting recovery of the infant CB in the face of premature birth, glucocorticoid treatment or other injuries including hemorrhage.
Our specific aims are:
Aim 1. To determine the regenerative potential of cerebellar white matter Nestin+ stem cells.
Aim 2. To identify signaling pathways which are altered in Nestin+ stem cells during regeneration of the EGL.
Aim 3. To test whether SHH signaling or some of the identified pathways enhance recruitment of Nestin+ stem cells to a depleted EGL.

Public Health Relevance

Approximately 11% of all live births in the US are considered pre-term, and such births are the leading cause of long-term motor and cognitive deficits or death, with cerebellar hypoplasia being prominent in such infants. The regenerative capacity of cerebellar stem cells that we discover and signaling pathways we identify that regulate cerebellar regeneration should provide a basis to develop therapies for cerebellar hypoplasia, especially in pre-term babies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092096-04
Application #
9415402
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Wojcinski, Alexandre; Lawton, Andrew K; Bayin, N Sumru et al. (2017) Cerebellar granule cell replenishment postinjury by adaptive reprogramming of Nestin+ progenitors. Nat Neurosci 20:1361-1370
Joyner, Alexandra L (2016) From Cloning Neural Development Genes to Functional Studies in Mice, 30 Years of Advancements. Curr Top Dev Biol 116:501-15
Leto, Ketty; Arancillo, Marife; Becker, Esther B E et al. (2016) Consensus Paper: Cerebellar Development. Cerebellum 15:789-828