Atp13a5 Marker Reveals Pericyte Specification in The Mouse Central Nervous System.

ABSTRACT

Perivascular mural cells including vascular smooth cells (VSMCs) and pericytes are integral components of the vascular system. In the central nervous system (CNS), pericytes are also indispensable for the blood-brain barrier (BBB), blood-spinal cord barrier and blood-retinal barrier, and play key roles in maintaining cerebrovascular and neuronal functions. However, the functional specifications of pericytes between CNS and peripheral organs have not been resolved at the genetic and molecular levels. Hence, the generation of reliable CNS pericyte-specific models and genetic tools remains very challenging. Here, we report a new CNS pericyte marker in mice. This putative cation-transporting ATPase 13A5 (Atp13a5) marker was identified through single cell transcriptomics, based on its specificity to brain pericytes. We further generated a knock-in model with both tdTomato reporter and Cre recombinase. Using this model to trace the distribution of Atp13a5-positive pericytes in mice, we found that the tdTomato reporter reliably labels the CNS pericytes, including the ones in spinal cord and retina but not peripheral organs. Interestingly, brain pericytes are likely shaped by the developing neural environment, as Atp13a5-positive pericytes start to appear around murine embryonic day 15 (E15) and expand along the cerebrovasculature. Thus, Atp13a5 is a specific marker of CNS pericyte lineage, and this Atp13a5-based model is a reliable tool to explore the heterogeneity of pericytes and BBB functions in health and diseases.Significance Statement Pericyte is a key component of the blood-brain barrier (BBB) and highly implicated in neurological and neurodegenerative diseases. However, current genetic tools for brain pericytes often come with limitations, due to the lack of specificity to the pericytes in the brain or central nervous system (CNS), as well as the overlap with other cell types, particularly vascular smooth muscle cells. Here, we identified that Atp13a5 is a CNS-specific pericyte marker based on mouse single-cell transcriptomics, and further validate it using a knock-in model carrying Atp13a5-driven tdTomato reporter and Cre recombinase. The success of the Atp13a5-based model opens new possibility of genetic manipulations targeting only CNS pericytes in vivo and studying their biology and functions in health and diseases more specifically.