The H(+) vacuolar ATPase maintains neural stem cells in the developing mouse cortex
Christian Lange1, Silvia Prenninger, Philip Knuckles
1DFG-Research Center and Cluster of Excellence for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany.
Abstract:
The vacuolar H(+) ATPase (v-ATPase) is crucial for endosome acidification, endocytosis, and trafficking in essentially all eukaryotic cells. Recent studies have shown that inhibition of the v-ATPase also leads to downregulation of important signaling pathways, including Notch and Wnt, which are key regulators of cell differentiation and tissue homeostasis across the animal kingdom. However, the requirement of endosome acidification and endocytosis in the transduction of Notch signaling is still highly debated. Moreover, no study has yet investigated the role of the v-ATPase during mammalian development. Here we show that expression of a dominant-negative subunit of the v-ATPase in neural precursors of the developing mouse cortex depleted neural stem cells by promoting their differentiation and the generation of neurons. Moreover, inhibition of the v-ATPase reduced endogenous Notch signaling and prevented the proliferative effect of a transmembrane, γ-secretase-dependent, active Notch without blocking the effects of its cytoplasmic intracellular domain (NICD). Our data are consistent with recent reports in Drosophila in which the v-ATPase has been suggested to be important for the transduction of Notch signaling. By extending these reports to mammalian embryos, our data may contribute to a better understanding of the role of the v-ATPase, endosome acidification, and endocytosis in signal transduction during neural stem cell differentiation and brain development.
Insights
The vacuolar H(+) ATPase (v-ATPase) is vital for cell processes. Inhibiting v-ATPase in developing mouse brains promotes neural stem cell differentiation and neuron generation.
Area of Science:
- Cell Biology
- Developmental Biology
- Neuroscience
Background:
- The vacuolar H(+) ATPase (v-ATPase) is essential for endosome acidification, endocytosis, and intracellular trafficking in eukaryotic cells.
- Recent studies link v-ATPase inhibition to the downregulation of signaling pathways like Notch and Wnt, crucial for cell differentiation and tissue homeostasis.
- The precise role of endosome acidification and endocytosis in Notch signaling transduction remains debated, with no prior studies on v-ATPase in mammalian development.
Purpose of the Study:
- To investigate the role of the v-ATPase in mammalian development, specifically in neural stem cell differentiation.
- To determine if v-ATPase inhibition affects Notch signaling during embryonic brain development.
- To elucidate the involvement of endosome acidification and endocytosis in Notch signaling transduction.
Main Methods:
- Expression of a dominant-negative v-ATPase subunit in neural precursors of developing mouse cortex.
- Analysis of neural stem cell populations and neuronal generation.
- Assessment of endogenous Notch signaling levels and response to active Notch signaling (transmembrane vs. NICD).
Main Results:
- Inhibition of v-ATPase in developing mouse cortex neural precursors led to depletion of neural stem cells.
- v-ATPase inhibition promoted neural stem cell differentiation and increased neuron generation.
- Reduced endogenous Notch signaling and blocked the proliferative effect of transmembrane Notch, but not NICD, indicating a role in Notch pathway activation upstream of NICD release.
Conclusions:
- The v-ATPase plays a critical role in mammalian brain development by regulating neural stem cell differentiation.
- Endosome acidification mediated by v-ATPase is necessary for proper transduction of Notch signaling in mammalian embryos.
- These findings extend observations from Drosophila, highlighting the conserved importance of v-ATPase in Notch signaling and neural development.
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