{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPHOX2B is a highly conserved paired‐like homeobox transcription factor that plays a master regulatory role in the development of the autonomic nervous system (ANS). It is expressed in both central and peripheral neural crest derivatives and is essential for the proper formation of neural circuits involved in respiratory rhythm and chemosensory control. Experimental evidence from human embryogenesis and animal models demonstrates that PHOX2B expression in regions such as the medullary parafacial area and retrotrapezoid nucleus is critical for establishing the circuitry that governs ventilatory responses and autonomic functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in PHOX2B—including polyalanine expansions as well as missense and frameshift alterations—disrupt its normal transcriptional activity, protein folding, and autoregulatory capabilities. Such alterations are responsible for a spectrum of disorders, most notably congenital central hypoventilation syndrome (CCHS), which may occur alone or in combination with conditions such as Hirschsprung disease and neuroblastoma. Functional studies indicate that even moderate expansions in the polyalanine tract can impair the capacity of PHOX2B to bind target DNA sequences and activate downstream gene expression, thereby accounting for the variable clinical presentations associated with these mutations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its pivotal developmental role, PHOX2B functions as a key transcriptional regulator by engaging in auto‐regulation and orchestrating the expression of critical target genes—such as dopamine β‐hydroxylase (DBH) and TLX2—that are necessary for noradrenergic differentiation and the establishment of sympathetic neuronal identity. Disruption of these transcriptional networks, including potential interactions with other oncogenic factors (for example, through interplay with ALK in neuroblastoma), underscores the broader impact of altered PHOX2B activity on both cell fate specification and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvanced studies have further unraveled the multifaceted roles of PHOX2B by highlighting the importance of gene dosage, post‐transcriptional regulation, and interaction with broader developmental and oncogenic networks. Together, clinical observations and mechanistic insights demonstrate that deviations in PHOX2B function—whether through impaired auto‐regulation, loss of transcriptional activity, or altered downstream signaling—lead to severe defects in autonomic control, predispose individuals to life‐threatening respiratory disorders in the neonatal period, and increase the risk for neuroblastoma later in life. This integrated view firmly establishes PHOX2B as a central molecular determinant whose proper function is indispensable for the differentiation and maintenance of the ANS."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M Garcia-Barceló, M H Sham, V C H Lui, et al. 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