ABSTRACT
YAP and TAZ are effectors of the Hippo pathway that controls multicellular development by integrating chemical and mechanical signals. Peripheral nervous system development depends on the Hippo pathway. We previously showed that loss of YAP and TAZ impairs the development of peripheral nerve as well as Schwann cell myelination. The role of the Hippo pathway in peripheral nerve regeneration has just started to be explored. After injury, Schwann cells adopt new identities to promote regeneration by converting to a repair-promoting phenotype. While the reprogramming of Schwann cells to repair cells has been well characterized, the maintenance of such repair phenotype cannot be sustained for a very long period, which limits nerve repair in human. First, we show that short or long-term myelin maintenance is not affected by defect in YAP and TAZ expression. Using crush nerve injury and conditional mutagenesis in mice, we also show that YAP and TAZ are regulators of repair Schwann cell proliferation and differentiation. We found that YAP and TAZ are required in repair Schwann cells for their redifferentiation into myelinating Schwann cell following crush injury. In this present study, we describe how the Hippo pathway and YAP and TAZ regulate remyelination over time during peripheral nerve regeneration.
Subject(s)
Adaptor Proteins, Signal Transducing , Hippo Signaling Pathway , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Cycle Proteins , Cell Differentiation , Cell Proliferation , Mice , Nerve Regeneration , Schwann Cells/metabolismABSTRACT
The basal forebrain cholinergic system projects broadly throughout the cortex and constitutes a critical source of neuromodulation for arousal and attention. Traditionally, this system was thought to function diffusely. However, recent studies have revealed a high degree of spatiotemporal specificity in cholinergic signaling. How the organization of cholinergic afferents confers this level of precision remains unknown. Here, using intersectional genetic fate mapping, we demonstrate that cholinergic fibers within the mouse cortex exhibit remarkable laminar and regional specificity and that this is organized in accordance with cellular birthdate. Strikingly, birthdated cholinergic projections within the cortex follow an inside-out pattern of innervation. While early born cholinergic populations target deep layers, late born ones innervate superficial laminae. We also find that birthdate predicts cholinergic innervation patterns within the amygdala, hippocampus, and prefrontal cortex. Our work reveals previously unappreciated specificity within the cholinergic system and the developmental logic by which these circuits are assembled.
Subject(s)
Basal Forebrain/physiology , Cholinergic Neurons/physiology , Age Factors , Animals , Basal Forebrain/anatomy & histology , Brain Mapping , Female , Male , Mice , Mice, Inbred Strains , Neural Pathways/anatomy & histology , Neural Pathways/physiology , Somatosensory Cortex/anatomy & histology , Somatosensory Cortex/physiologyABSTRACT
[This corrects the article DOI: 10.3389/fnmol.2019.00177.].
