{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dispatched 1 (DISP1) is a multispan transmembrane protein that plays a central role in the release of dual‐lipidated Hedgehog (Hh) ligands from producing cells. Structural and biochemical studies have shown that DISP1 comprises 12 transmembrane helices and two extracellular domains that adopt an “open” conformation, allowing it to engage the lipid‐modified Hh ligand. In fact, DISP1 undergoes a specific proteolytic cleavage event that removes steric hindrance in its extracellular region and facilitates binding of the cholesterol‐modified Hh, thereby promoting its hand‐off to secreted carrier proteins such as those in the Scube family (see, for example"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In mouse models, DISP1 is indispensable for moving Sonic Hedgehog (Shh) away from its synthesis sites, thereby enabling long‐range signaling that is essential for ventral neural tube patterning and proper specification of cell types during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Disruptive mutations in DISP1 have been associated with midline developmental defects—including those seen in holoprosencephaly—as well as with microdeletion syndromes mapping to the 1q41–q42 region, although DISP1 haploinsufficiency alone may not explain the full spectrum of these phenotypes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, functional insights into DISP1 have been extended by structural analyses that capture its ligand‐bound state and highlight cholesterol-like molecules present within its transmembrane domains, supporting a transporter‐like role for moving the hydrophobic Hh ligand."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Beyond its developmental functions, genetic studies have hinted at a broader influence of DISP1 on neuropsychiatric phenotypes: polymorphisms in regions near DISP1 have been associated with treatment responses in disorders such as obsessive–compulsive disorder"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and bipolar disorder."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Comparative genomic analyses within the DISP gene family—including identification of related homologs like DISP3—underscore conserved domains that are critical for the release of lipid‐anchored secreted proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, studies examining candidate gene deletions in patients with holoprosencephaly and related midline deficiencies, as well as animal models such as the chick talpid2 mutant, further support the importance of correct DISP1 function for proper embryonic patterning"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In addition, selection signature studies in livestock have identified DISP1 as a notable candidate gene, reflecting its potential impact on developmental and physiological traits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Collectively, these findings establish DISP1 as a key mediator of Hh ligand release, influencing not only early embryogenesis and neural patterning but also, potentially, adult neurobehavioral traits.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hanna Tukachinsky, Ryan P Kuzmickas, Cindy Y Jao, et al. 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