Synovial joint cavitation during mouse embryo limb skeletogenesis entails Na/K-ATPase pump expression and osmoregulatory activity
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ABSTRACT:
PROVIDER: PRJNA1157826 | ENA |
REPOSITORIES: ENA
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Project description:The developmental biology of limb synovial joints and their water/lubricant-filled cavity remains unclear. Joint formation is known to start with emergence at each prescribed anatomical site of a compacted Gdf5-expressing mesenchymal interzone flanked by cartilaginous skeletal primordia. We and others previously showed that the interzone cells serve as progenitors and generate most joint tissues over time, including articular cartilage and ligaments. But how is the cavity formed within the compacted interzone? Because water accrual would be needed to create and inflate the cavity and in turn distance the flanking skeletal elements, cavity formation may require energy-consuming osmoregulatory mechanisms able to draw water and exert mechanical force. Our data now reveal that interzone cells in cavitating knee and digit mouse embryo joints strongly express the Na/K-ATPase pumps Atp1a1, Atp1b1 and Atp1b3, members of a key cell surface osmoregulatory protein family that regulates fluid tonicity and drawing of water. There was also local and specific expression of the water channel Aquaporin 1 (Aqp1). Single cell RNA seq (scRNAseq) showed that Gdf5+ interzone cells expressing those genes culminated in number at cavitation and were characterized by other osmoregulatory and mechano-sensing genes also. Indeed, when pregnant mice were administered ouabain -a physiological glycoside that normally limits Na/K-ATPase pump activity and osmoregulatory processes-, limb joint cavitation in the embryos was inhibited as was lubricant gene expression. Joint development is known to depend on signals from Indian hedgehog-expressing growth plate chondrocytes in flanking skeletal primordia. Interference with hedgehog signaling did coordinately inhibit expression of pump, mechano-sensing and lubricant genes as well as cavitation. Together, our data suggest a novel understanding of joint cavitation as an active energy-requiring osmoregulatory process able to accrue a water-based fluid, distance the flanking articulating surfaces and establish a synovial cavity in close coordination with long bone development and growth.
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Project description:Recent genetic evidence implicates the serine/threonine kinase cyclin G-associated kinase (GAK) as a Parkinson’s disease risk. However, its role in neuronal function and many downstream effectors remain unclear. Employing a chemical genetics method, we show here that the sodium potassium pump (Na+/K+-ATPase) is a GAK target in the brain. We further show that GAK modulates Na+/K+-ATPase at a novel site affecting both pump localization and function. Whole-cell patch clamp recordings from CA1 pyramidal cells in GAK conditional knockout mice show a larger change in resting membrane potential when exposed to the Na+/K+-ATPase blocker, ouabain, indicating altered Na+/K+-ATPase function in GAK knockouts. Additionally, we show that GAK-deficient neurons have enlarged dendritic spines and we identify the spine associated protein Sipa1L1 (or SPAR) as a GAK target, which may contribute to this effect. Our results reveal novel functions of GAK in neurons.
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