Gpr125 identifies myoepithelial progenitors at tips of lacrimal ducts and is essential for tear film

Abstract

Gpr125, encoded by Adgra3, is an orphan adhesion G-protein coupled receptor (aGPCR) implicated in Wnt signaling and planar polarity. Here we establish both physiological and pathological roles for Gpr125. We show that mice lacking Gpr125 display an ocular phenotype with many hallmarks of human dry eye disease. These include squinting, abnormal lacrimation, mucus accumulation, swollen eyelids and inflammatory infiltration of lacrimal and meibomian glands. We further demonstrate that mice expressing Gpr125 lacking six transmembrane and the cytoplasmic domain recapitulate the null phenotype, indicating that downstream signaling is essential. Utilizing a Gpr125-β-gal reporter and scRNAseq, we identify Gpr125 expression in a discrete population of embryonic myoepithelial cells located at the tips of developing lacrimal ducts. By lineage tracing we show these cells function as progenitors of the adult lacrimal myoepithelium. Beyond defining an essential role for Gpr125 in tear film and identifying its utility as a marker of lacrimal progenitors, this study implicates Gpr125 in the etiology of dry eye disease, and defines novel animal models of this common malady.

Loss of Adgra3 causes obstructive azoospermia with high penetrance in male mice

“…In the present study, half of the mice lacking Adgra3 were infertile due to obstructive azoospermia, resulting from effects on the epithelial lining of the male reproductive and the accessory organs rather than a direct testicular phenotype. ADGRA3 has been reported as a spermatogonial stem cell marker, 25,26,41 and our data support its expression in spermatogonia as ADGRA3. In line with a previous study showing spermatogonial stem cells maintaining progenitor stem cell properties despite deletion of the cytoplasmic domain of Adgra3, 26 we found no major change in germ cell numbers, spermatogenesis, sperm count, motility or morphology following loss of Adgra3.…”

“…Adgra3 expression was present within both the epididymis, through the efferent tubules and into the testis (Figure 1H) and was confirmed in the edge of the seminiferous tubules (Figure 1I). 25,26,41 Furthermore, Adgra3 expression was also detected in the renal cortex (Figure 1J).…”

“…ADGRA3 (GPR125) is an orphan member of the aGPCR family 18 with which it shares the characteristic aGPCRs domains, including the GAIN domain, multiple leucine‐rich repeats (LRR), an immunoglobulin‐like domain (Ig), and a hormone‐binding domain (HBD) (Figure 1A). 18 ADGRA3 was initially identified as a spermatogonial stem cell marker in multiple species 25–27 . Later studies showed an increase in Adgra3 expression within the choroid plexus after acute brain injury 28 and demonstrated an essential role of ADGRA3 in murine mammary and lacrimal gland development 29,30 .…”

“… 18 ADGRA3 was initially identified as a spermatogonial stem cell marker in multiple species. 25 , 26 , 27 Later studies showed an increase in Adgra3 expression within the choroid plexus after acute brain injury 28 and demonstrated an essential role of ADGRA3 in murine mammary and lacrimal gland development. 29 , 30 ADGRA3 internalizes constitutively, 31 recruits disheveled proteins to the membrane, and modulates the Wnt/β‐catenin pathway via regulation of β‐catenin transcriptional activity.…”