{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:22:48Z","timestamp":1783077768379,"version":"3.54.6"},"posted":{"date-parts":[[2026,5,31]]},"reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T00:00:00Z","timestamp":1780185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01NS039996"],"award-info":[{"award-number":["R01NS039996"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R24OD010943"],"award-info":[{"award-number":["R24OD010943"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Interoceptive paraneurons are neuron-like cells located within internal epithelial cell surfaces that sense internal stimuli to evoke specific behavioral or physiological responses. The elucidation of terminal differentiation programs of paraneurons is expected to provide insights into how epithelial cells acquire neuron-like feature during development and possibly also over evolutionary time. We define here transcriptional programs that control the terminal differentiation of an interoceptive paraneuron class in the nematode\n                  <jats:italic>C. elegans<\/jats:italic>\n                  , called uv1. The uv1 cells sense mechanosensory inputs in the uterus and signal via the HSN neurons to modulate egg-laying behavior. We show that like in canonical neurons, the neuron-like secretory features of uv1 are controlled by a combination of CUT homeobox genes, while the combinatorial terminal gene battery that defines the unique functional features of uv1 is jointly controlled by a combination of at least three transcription factors, a LIM homeodomain (LIN-11), a SoxD (EGL-13) and a Pax family (EGL-38) protein. These factors act in a terminal selector-type manner to jointly co-regulate the many distinct uv1-paraneuron specific molecular features, such as sensory receptors, neuromodulatory receptors and neuropeptides, as well as uv1\u2019s tyraminergic identity. Our findings demonstrate notable similarities in the dichotomous architecture of gene regulatory programs of neurons and paraneurons.\n                <\/jats:p>","DOI":"10.64898\/2026.05.28.728471","type":"posted-content","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T21:25:11Z","timestamp":1780262711000},"source":"Crossref","is-referenced-by-count":0,"title":["Regulatory architecture controlling terminal differentiation of an interoceptive paraneuron in\n                  <i>C. elegans<\/i>"],"prefix":"10.64898","author":[{"given":"Hongzhu","family":"Ji","sequence":"first","affiliation":[{"name":"Columbia University, Department of Biological Sciences, Howard Hughes Medical Institute, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Vidal","sequence":"additional","affiliation":[{"name":"Columbia University, Department of Biological Sciences, Howard Hughes Medical Institute, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Conklin","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana-Champaign, Department of Crop Sciences, Urbana IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tergel","family":"Enkhtuvshin","sequence":"additional","affiliation":[{"name":"Columbia University, Department of Biological Sciences, Howard Hughes Medical Institute, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan E.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"University of Illinois at Urbana-Champaign, Department of Crop Sciences, Urbana IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7634-2854","authenticated-orcid":false,"given":"Oliver","family":"Hobert","sequence":"additional","affiliation":[{"name":"Columbia University, Department of Biological Sciences, Howard Hughes Medical Institute, New York, NY 10027"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026070303300931000_2026.05.28.728471v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.02.024"},{"key":"2026070303300931000_2026.05.28.728471v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2015.10.005"},{"key":"2026070303300931000_2026.05.28.728471v2.3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006697"},{"key":"2026070303300931000_2026.05.28.728471v2.4","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2018.00088"},{"key":"2026070303300931000_2026.05.28.728471v2.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038011"},{"key":"2026070303300931000_2026.05.28.728471v2.6","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1242\/dev.120.10.2713","article-title":"The lin-3\/let-23 pathway mediates inductive signalling during male spicule development in Caenorhabditis elegans","volume":"120","year":"1994","journal-title":"Development"},{"key":"2026070303300931000_2026.05.28.728471v2.7","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.20.3919"},{"key":"2026070303300931000_2026.05.28.728471v2.8","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80112-2"},{"key":"2026070303300931000_2026.05.28.728471v2.9","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1093\/genetics\/165.3.1623","article-title":"The EGL-13 SOX domain transcription factor affects the uterine pi cell lineages in Caenorhabditis elegans","volume":"165","year":"2003","journal-title":"Genetics"},{"key":"2026070303300931000_2026.05.28.728471v2.10","doi-asserted-by":"crossref","unstructured":"Collins, K. M. , Bode, A. , Fernandez, R. W. , Tanis, J. E. , Brewer, J. C. , Creamer, M. S. and Koelle, M. R. (2016). Activity of the C. elegans egg-laying behavior circuit is controlled by competing activation and feedback inhibition. eLife 5,.","DOI":"10.7554\/eLife.21126.020"},{"key":"2026070303300931000_2026.05.28.728471v2.11","doi-asserted-by":"crossref","unstructured":"Eroglu, M. , Yu, B. and Derry, W. B. (2023). Efficient CRISPR\/Cas9 mediated large insertions using long single-stranded oligonucleotide donors in C. elegans. The FEBS journal.","DOI":"10.1101\/2022.09.26.509570"},{"key":"2026070303300931000_2026.05.28.728471v2.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1357-20.2020"},{"key":"2026070303300931000_2026.05.28.728471v2.13","doi-asserted-by":"crossref","first-page":"dev204958","DOI":"10.1242\/dev.204958","article-title":"Pervasive homeobox gene function in the male-specific nervous system of Caenorhabditis elegans","volume":"152","year":"2025","journal-title":"Development"},{"key":"2026070303300931000_2026.05.28.728471v2.14","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00894"},{"key":"2026070303300931000_2026.05.28.728471v2.15","first-page":"1","article-title":"Concept of Paraneurons","volume":"40","year":"1977","journal-title":"Arch. histol. jap"},{"key":"2026070303300931000_2026.05.28.728471v2.16","doi-asserted-by":"crossref","unstructured":"Fujita, T. , Kanno, T. and Kobayashi, S. (1988). The Paraneuron. Tokyo: Springer.","DOI":"10.1007\/978-4-431-68066-6"},{"key":"2026070303300931000_2026.05.28.728471v2.17","unstructured":"Gupta, B. P. , Hanna-Rose, W. and Sternberg, P. W. (2012). Morphogenesis of the vulva and the vulval-uterine connection. WormBook 1\u201320."},{"key":"2026070303300931000_2026.05.28.728471v2.18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1242\/dev.126.1.169","article-title":"COG-2, a sox domain protein necessary for establishing a functional vulval-uterine connection in Caenorhabditis elegans","volume":"126","year":"1999","journal-title":"Development"},{"key":"2026070303300931000_2026.05.28.728471v2.19","doi-asserted-by":"crossref","unstructured":"Hills-Muckey, K. , Martinez, M. A. Q. , Stec, N. , Hebbar, S. , Saldanha, J. , Medwig-Kinney, T. N. , Moore, F. E. Q. , Ivanova, M. , Morao, A. , Ward, J. D. , et al. (2022). An engineered, orthogonal auxin analog\/AtTIR1(F79G) pairing improves both specificity and efficacy of the auxin degradation system in Caenorhabditis elegans. Genetics 220,.","DOI":"10.1093\/genetics\/iyab174"},{"key":"2026070303300931000_2026.05.28.728471v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2015.12.007"},{"key":"2026070303300931000_2026.05.28.728471v2.21","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/s41583-021-00497-x","article-title":"Homeobox genes and the specification of neuronal identity","volume":"22","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"2026070303300931000_2026.05.28.728471v2.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2025.09.072"},{"key":"2026070303300931000_2026.05.28.728471v2.23","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.12.2337"},{"key":"2026070303300931000_2026.05.28.728471v2.24","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.106.065516"},{"key":"2026070303300931000_2026.05.28.728471v2.25","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20189"},{"key":"2026070303300931000_2026.05.28.728471v2.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2022.02.040"},{"key":"2026070303300931000_2026.05.28.728471v2.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01216-1"},{"key":"2026070303300931000_2026.05.28.728471v2.28","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2003.68.159"},{"key":"2026070303300931000_2026.05.28.728471v2.29","doi-asserted-by":"publisher","DOI":"10.1242\/DEV.122.11.3617"},{"key":"2026070303300931000_2026.05.28.728471v2.30","doi-asserted-by":"crossref","first-page":"5319","DOI":"10.1242\/dev.126.23.5319","article-title":"The lin-11 LIM domain transcription factor is necessary for morphogenesis of C. elegans uterine cells","volume":"126","year":"1999","journal-title":"Development"},{"key":"2026070303300931000_2026.05.28.728471v2.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.08.068"},{"key":"2026070303300931000_2026.05.28.728471v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2618-9"},{"key":"2026070303300931000_2026.05.28.728471v2.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010372"},{"key":"2026070303300931000_2026.05.28.728471v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"2026070303300931000_2026.05.28.728471v2.35","doi-asserted-by":"crossref","unstructured":"Sepers, J. J. , Verstappen, N. H. M. , Vo, A. A. , Ragle, J. M. , Ruijtenberg, S. , Ward, J. D. and Boxem, M. (2022). The mIAA7 degron improves auxin-mediated degradation in Caenorhabditiselegans. G3 (Bethesda) 12,.","DOI":"10.1093\/g3journal\/jkac222"},{"key":"2026070303300931000_2026.05.28.728471v2.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.07.031"},{"key":"2026070303300931000_2026.05.28.728471v2.37","doi-asserted-by":"crossref","first-page":"102901","DOI":"10.1016\/j.xpro.2024.102901","article-title":"Protocol to synthesize the auxin analog 5-Ph-IAA for conditional protein depletion in C. elegans using the AID2 system","volume":"5","year":"2024","journal-title":"STAR Protoc"},{"key":"2026070303300931000_2026.05.28.728471v2.38","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1989-09.2009"},{"key":"2026070303300931000_2026.05.28.728471v2.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.02.040"},{"key":"2026070303300931000_2026.05.28.728471v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13135"},{"key":"2026070303300931000_2026.05.28.728471v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-66536-2"},{"key":"2026070303300931000_2026.05.28.728471v2.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2004218"},{"key":"2026070303300931000_2026.05.28.728471v2.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2019.103566"},{"key":"2026070303300931000_2026.05.28.728471v2.44","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0678-24.2024"},{"key":"2026070303300931000_2026.05.28.728471v2.45","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2020.12.012"},{"key":"2026070303300931000_2026.05.28.728471v2.46","unstructured":"Young, A. F. , Schmidt, H. F. and Sundaram, M. V. (2022). Molecular lesions in alleles of the Caenorhabditis elegans lin-11 gene. MicroPubl Biol 2022,."},{"key":"2026070303300931000_2026.05.28.728471v2.47","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20000101)429:1<127::AID-CNE10>3.0.CO;2-H"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.28.728471","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:30:36Z","timestamp":1783074636000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.28.728471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,31]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.05.28.728471","relation":{},"subject":[],"published":{"date-parts":[[2026,5,31]]},"subtype":"preprint"}}