Matrongolo, M. J. | Search bioRxiv

bioRxiv2023

Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/-:5xFAD transgenic Alzheimers disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

neuroscience↗

bioRxiv2022

Twist1 and balanced retinoic acid signaling act to suppress cortical folding in mice

Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss of Twist1 expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Maternal retinoic acid supplementation rescues cortical folding and sulci formation. Our results suggest that balanced retinoic acid signaling from the meninges is required to maintain lissencephaly in mice, and in a manner independent from neuroprogenitor cell amplification.

neuroscience↗