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The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides. Functional genomic approaches underpinned by <jats:italic>in vitro<\/jats:italic> culture of juvenile <jats:italic>Fasciola hepatica<\/jats:italic> facilitate control target validation in the most pathogenic life stage. Comparative transcriptomics of <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> maintained 21 day old <jats:italic>F<\/jats:italic>. <jats:italic>hepatica<\/jats:italic> finds that 86% of genes are expressed at similar levels across maintenance treatments suggesting commonality in core biological functioning within these juveniles. Phenotypic comparisons revealed higher cell proliferation and growth rates in the <jats:italic>in vivo<\/jats:italic> juveniles compared to their <jats:italic>in vitro<\/jats:italic> counterparts. These phenotypic differences were consistent with the upregulation of neoblast-like stem cell and cell-cycle associated genes in <jats:italic>in vivo<\/jats:italic> maintained worms. The more rapid growth\/development of <jats:italic>in vivo<\/jats:italic> juveniles was further evidenced by a switch in cathepsin protease expression profiles, dominated by cathepsin B in <jats:italic>in vitro<\/jats:italic> juveniles and by cathepsin L in <jats:italic>in vivo<\/jats:italic> juveniles. Coincident with more rapid growth\/development was the marked downregulation of both classical and peptidergic neuronal signalling components in <jats:italic>in vivo<\/jats:italic> maintained juveniles, supporting a role for the nervous system in regulating liver fluke growth and development. Differences in the miRNA complements of <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> juveniles identified 31 differentially expressed miRNAs, including <jats:italic>fhe-let-7a-5p<\/jats:italic>, <jats:italic>fhe-mir-124-3p<\/jats:italic> and miRNAs predicted to target Wnt-signalling, which supports a key role for miRNAs in driving the growth\/developmental differences in the <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> maintained juvenile liver fluke. Widespread differences in the expression of neuronal genes in juvenile fluke grown <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> expose significant interplay between neuronal signalling and the rate of growth\/development, encouraging consideration of neuronal targets in efforts to dysregulate growth\/development for parasite control.<\/jats:p>","DOI":"10.1371\/journal.pntd.0010854","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T18:24:30Z","timestamp":1667845470000},"page":"e0010854","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Transcriptomic analysis supports a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9853-9036","authenticated-orcid":true,"given":"Emily","family":"Robb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"McCammick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan","family":"Wells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"McVeigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Gardiner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"McCusker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mousley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki J.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron G.","family":"Maule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"pntd.0010854.ref001","article-title":"The \u201cNeglected\u201d Neglected Worms","author":"World Health Organisation","year":"2007","journal-title":"Action Against Worms"},{"key":"pntd.0010854.ref002","first-page":"465","volume-title":"by. 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