{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRXFP2 is a G protein–coupled receptor that serves as the cognate binding partner for insulin‐like peptide 3 (INSL3) and, under certain conditions, relaxin. A large body of work establishes its essential function in male reproductive development, particularly during testicular descent, where genetic mutations or splice‐variant alterations (including the recurrent T222P mutation) can lead to cryptorchidism and related gonadal dysgenesis. Moreover, disruption of RXFP2 signaling has been linked not only to maldescent of the testes but also to anomalies in germ cell function and male fertility. Collectively, these studies support a critical developmental role for RXFP2 in the reproductive system and underscore its relevance in clinical conditions such as anorchia and cryptorchidism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, RXFP2 exhibits a complex architecture characterized by an extensive extracellular domain with leucine‐rich repeats and a unique N‐terminal low–density lipoprotein class A (LDLa) module that is indispensable for signal transduction. Detailed structure–function analyses have demonstrated that while the primary hormone binding relies on B‐chain residues of INSL3 (and in some cases relaxin), efficient receptor activation, cAMP signaling, and downstream responses depend on the integrity of the LDLa module and proper receptor processing. Investigations using splice variants, point mutations, and receptor chimeras have further clarified that minor changes in the extracellular domain can completely abrogate signaling despite preserved ligand binding, thereby highlighting the intricate molecular mechanisms underlying RXFP2 activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in reproductive development, emerging evidence demonstrates that RXFP2 signaling has broader physiological and pathophysiological implications. In adults, RXFP2 activation influences bone metabolism, as mutations have been associated with reduced bone density, and it is expressed in osteoblasts where it modulates cell proliferation and differentiation. RXFP2 is also found in other tissues such as the ocular surface and spermatozoa, where it contributes to corneal wound healing and confers anti‐apoptotic as well as antioxidant effects that may enhance sperm motility and genomic integrity. Furthermore, recent genetic and pharmacological studies have implicated RXFP2 in cardiovascular regulation—in particular, in the context of resistant hypertension—thus proposing RXFP2 antagonism as a novel therapeutic avenue. Though its role in other conditions such as varicosis remains to be fully elucidated, the multifaceted actions of RXFP2 continue to emerge, highlighting its potential as a drug target in reproductive, skeletal, and cardiovascular disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alberto Ferlin, Mauro Simonato, Lucia Bartoloni, et al. 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