Biology subjects

Coombs, A. M.

Publications and source records attributed to Coombs, A. M..

3 recordsLinked to original sources

bioRxiv2026

PIEZOs regulate oligodendrocyte sheath formation, expansion, and myelination potential

Myelination requires precise integration of physical cues by oligodendrocyte lineage cells (OLCs), but the molecular sensors that detect these cues remain incompletely understood. Here, we demonstrate that oligodendrocyte progenitor cells (OPCs) are sensitive to sub-micron changes in membrane displacement. Based on channel properties, RNA expression, and protein abundance, we find that the mechanosensitive ion channel PIEZO1 contributes to OPC mechanosensitivity. In vivo, zebrafish with oligodendrocyte (OL)-specific disruption of piezo1 have fewer sheaths per OL. Zebrafish with OL-specific piezo2 disruption also have fewer sheaths as well as decreased total myelin capacity over time. OL-specific disruption of both piezo1 and piezo2 caused more severe phenotypes, with reduced OPC volume, and in myelinating OLs, reduced sheath number, sheath length, and total myelin output. Furthermore, piezo1/piezo2 disruption leads to sporadic sheath formation outside the normal developmental window. Our findings indicate that OLs use Piezo channels in vivo to influence sheath formation, expansion, and retractions.

neuroscience↗

bioRxiv2024

TMEM63A, associated with hypomyelinating leukodystrophies, is an evolutionarily conserved regulator of myelination

Infantile hypomyelinating leukodystrophy 19 (HLD19) is a rare genetic disorder where patients exhibit reduced myelin in central nervous system (CNS) white matter tracts and present with varied neurological symptoms. The causative gene TMEM63A encodes a mechanosensitive ion channel whose role in myelination has not been explored. Our study shows that TMEM63A is a major regulator of OL-driven myelination in the CNS. In mouse and zebrafish, Tmem63a inactivation led to early deficits in myelination, recapitulating the HLD19 phenotype. OL-specific conditional mouse knockouts of Tmem63a exhibited transient reductions in myelin, indicating that TMEM63A regulates myelination cell-autonomously. We show that TMEM63A is present at plasma membrane and on lysosomes and modulates myelin/myelin-associated protein production. Intriguingly, HLD19-associated TMEM63A variants from patients blocked trafficking to cell membrane. Together, our results reveal an ancient role for TMEM63A in fundamental aspects of myelination in vivo and highlight two exciting new models for the development of treatments for devastating hypomyelinating leukodystrophies.

neuroscience↗

bioRxiv2020

PIEZO ion channel is required for root mechanotransduction in Arabidopsis thaliana

Plant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show that Arabidopsis thaliana PIEZO (AtPIEZO) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO is highly expressed in the columella and lateral root cap cells of the root tip which experience robust mechanical strain during root growth. Deleting PIEZO from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild type plants. piezo mutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of AtPIEZO in root mechanotransduction. Finally, a chimeric PIEZO channel that includes the C-terminal half of AtPIEZO containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest that Arabidopsis PIEZO plays an important role in root mechanotransduction and establishes PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.

plant biology↗