{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T11:18:38Z","timestamp":1767611918326,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Hrvatska Zaklada za Znanost","doi-asserted-by":"publisher","award":["IP-06-2016-2575"],"award-info":[{"award-number":["IP-06-2016-2575"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Science, Education and Sports of the Republic of Croatia","award":["021-2160528-0507"],"award-info":[{"award-number":["021-2160528-0507"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The expression of 5-HT (serotonin) receptors (sr) was analyzed in the spinal cord and ganglia of 15 human conceptuses (5\u201310-weeks), and in the 9-week fetus with spina bifida. We used immunohistochemical method to detect sr-positive, apoptotic (caspase-3) and proliferating (Ki-67) cells, double immunofluorescence for co-localization with protein gene peptide (pgp) 9.5 and GFAP, as well as semiquantification and statistical measurements. Following the neurulation process, moderate (sr1 and sr2) and mild (sr3) expression characterized neuroblasts in the spinal cord and ganglia. During further development, sr1 expression gradually increased in the motoneurons, autonomic and sensory neurons, while sr2 and sr3 increased strongly in floor and roof plates. In the ganglia, sr3 expression increased during limited developmental period, while sr1 and sr2 increased throughout the investigated period. Co-expression of sr\/pgp 9.5 characterized developing neurons, while sr\/GFAP co-localized in the roof plate. In the spinal cord and ganglia of malformed fetus, weaker sr1 and sr2 and stronger sr3 expression accompanied morphological abnormalities. Anomalous roof plate morphology showed an excess of apoptotic and proliferating cells and increased sr3 expression. Our results indicate a human-species specific sr expression pattern, and the importance of sr1 in neuronal differentiation, and sr2 and sr3 in the control of the roof plate morphogenesis in normal and disturbed development.<\/jats:p>","DOI":"10.3390\/ijms22147320","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T12:31:25Z","timestamp":1625661085000},"page":"7320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Expression Pattern of 5-HT (Serotonin) Receptors during Normal Development of the Human Spinal Cord and Ganglia and in Fetus with Cervical Spina Bifida"],"prefix":"10.3390","volume":"22","author":[{"given":"Hrvoje","family":"Punda","sequence":"first","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology, University Hospital in Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Snjezana","family":"Mardesic","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8943-4109","authenticated-orcid":false,"given":"Natalija","family":"Filipovic","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivona","family":"Kosovic","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Benzon","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-1026","authenticated-orcid":false,"given":"Marin","family":"Ogorevc","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3868-0828","authenticated-orcid":false,"given":"Ivana","family":"Bocina","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kresimir","family":"Kolic","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Interventional Radiology, University Hospital in Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2182-2890","authenticated-orcid":false,"given":"Katarina","family":"Vukojevic","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirna","family":"Saraga-Babic","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"ref_1","unstructured":"Saunders, W.B. (1994). Spinal Cord. Human Embryology, Bailliere Tindall."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF00185911","article-title":"The vertebrate tail bud: Three germ layers from one tissue","volume":"185","author":"Griffith","year":"1992","journal-title":"Anat. Embryol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/tera.1420480106","article-title":"Embryonic development of the mammalian caudal neural tube","volume":"48","author":"Nievelstein","year":"1993","journal-title":"Teratology"},{"key":"ref_4","first-page":"341","article-title":"Variations in the formation of the human caudal spinal cord","volume":"36","author":"Sapunar","year":"1995","journal-title":"J. Hirnforsch."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s004010050413","article-title":"Differences in origin and fate between the cranial and caudal spinal cord during normal and disturbed human development","volume":"91","author":"Krolo","year":"1996","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0940-9602(01)80220-X","article-title":"Morphological diversity of dying cells during regression of the human tail","volume":"183","author":"Sapunar","year":"2001","journal-title":"Ann. Anat. Anat. Anz. Off. Organ. Anat. Ges."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/aja.1001520108","article-title":"Evidence of a role for cell death in the disappearance of the embryonic human tail","volume":"152","author":"Fallon","year":"1978","journal-title":"Am. J. Anat."},{"key":"ref_8","first-page":"91","article-title":"Proliferation and differentiation of glial and neuronal progenitors in the development of human spinal ganglia","volume":"78","author":"Vukojevic","year":"2009","journal-title":"Differ. Res. Biol. Divers."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1002\/ar.23376","article-title":"Neuronal differentiation in the developing human spinal ganglia","volume":"299","author":"Vukojevic","year":"2016","journal-title":"Anat. Rec."},{"key":"ref_10","first-page":"777","article-title":"Neurochemical properties of sensory neurons in the development","volume":"99","author":"Masliukov","year":"2013","journal-title":"Ross. Fiziol. Zhurnal Im. I.M. Sechenova"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1159\/000014586","article-title":"Neurotransmitters and neuropeptides in the developing human central nervous system. A review","volume":"8","author":"Yew","year":"1999","journal-title":"Biol. Signals Recept."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5281","DOI":"10.2174\/092986711798184253","article-title":"Serotonin and its receptors in the human CNS with new findings\u2014A mini review","volume":"18","author":"Hung","year":"2011","journal-title":"Curr. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/syn.890140303","article-title":"Localization of 5-HT1A receptors to astroglial cells in adult rats: Implications for neuronal-glial interactions and psychoactive drug mechanism of action","volume":"14","author":"Clarke","year":"1993","journal-title":"Synapse"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1212\/WNL.0000000000000806","article-title":"Medullary serotonergic system: Organization, effects, and clinical correlations","volume":"83","author":"Benarroch","year":"2014","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0165-3806(95)00090-Z","article-title":"Somatostatin enhances neurofilament expression and neurite outgrowth in cultured rat cerebellar granule cells","volume":"88","author":"Taniwaki","year":"1995","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0165-3806(98)00142-4","article-title":"Central neuronal synapse formation on micropatterned surfaces","volume":"111","author":"Ma","year":"1998","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/(SICI)1097-4695(199606)30:2<255::AID-NEU7>3.0.CO;2-4","article-title":"Prevention of activity-dependent neuronal death: Vasoactive intestinal polypeptide stimulates astrocytes to secrete the thrombin-inhibiting neurotrophic serpin, protease nexin I","volume":"30","author":"Festoff","year":"1996","journal-title":"J. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/00019052-199812000-00007","article-title":"Biological interventions for spinal cord injury","volume":"11","author":"Privat","year":"1998","journal-title":"Curr. Opin. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0165-3806(98)00132-1","article-title":"Influence of hypergravity on the development of monoaminergic systems in the rat spinal cord","volume":"111","author":"Sandillon","year":"1998","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0006-8993(01)02749-4","article-title":"Subdural engraftment of serotonergic neurons following spinal hemisection restores spinal serotonin, downregulates serotonin transporter, and increases BDNF tissue content in rat","volume":"913","author":"Hains","year":"2001","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF00241357","article-title":"Fictive motor activities in adult chronic spinal rats transplanted with embryonic brainstem neurons","volume":"106","author":"Yakovleff","year":"1995","journal-title":"Exp. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.expneurol.2019.05.007","article-title":"Serotonergic mechanisms in spinal cord injury","volume":"318","author":"Perrin","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.conb.2014.12.008","article-title":"Serotonergic modulation of spinal motor control","volume":"33","author":"Perrier","year":"2015","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.neuron.2015.10.007","article-title":"Multi-Scale Molecular Deconstruction of the Serotonin Neuron System","volume":"88","author":"Okaty","year":"2015","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1111\/j.1471-4159.1986.tb13069.x","article-title":"Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain","volume":"46","author":"Middlemiss","year":"1986","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/0306-4522(90)90224-R","article-title":"Localization of acetylcholinesterase positive neurons and substance P and enkephalin positive fibers by histochemistry and immunohistochemistry in the sympathetic intermediate zone of the developing human spinal cord","volume":"39","author":"Luo","year":"1990","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.psychres.2010.05.003","article-title":"Profiles of serotonin receptors in the developing human thalamus","volume":"185","author":"Wai","year":"2011","journal-title":"Psychiatry Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.expneurol.2009.10.003","article-title":"5-HT precursor loading, but not 5-HT receptor agonists, increases motor function after spinal cord contusion in adult rats","volume":"221","author":"Hayashi","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.expneurol.2005.01.002","article-title":"Serotonergic fiber sprouting to external anal sphincter motoneurons after spinal cord contusion","volume":"193","author":"Holmes","year":"2005","journal-title":"Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.1523\/JNEUROSCI.23-10-04219.2003","article-title":"Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury","volume":"23","author":"Li","year":"2003","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1002\/ana.22527","article-title":"Recovery from chronic spinal cord contusion after Nogo receptor intervention","volume":"70","author":"Wang","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12119","DOI":"10.1038\/s41598-017-12449-6","article-title":"Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS","volume":"7","author":"Hirokawa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.neuron.2004.10.015","article-title":"Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury","volume":"44","author":"Kim","year":"2004","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/j.1460-9568.2004.03558.x","article-title":"Long-term changes in the molecular composition of the glial scar and progressive increase of serotoninergic fibre sprouting after hemisection of the mouse spinal cord","volume":"20","author":"Camand","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Carlson, B.M. (2014). Chapter 11 Nervous System. Human Embryology and Developmental Biology, Elsevier\/Saunders.","DOI":"10.1016\/B978-1-4557-2794-0.00011-5"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cne.903180102","article-title":"Serotoninergic, noradrenergic, and peptidergic innervation of Onuf\u2019s nucleus of normal and transected spinal cords of baboons (Papio papio)","volume":"318","author":"Rajaofetra","year":"1992","journal-title":"J. Comp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0079-6123(08)60278-2","article-title":"Transplantation of fetal serotonin neurons into the transected spinal cord of adult rats: Morphological development and functional influence","volume":"78","author":"Privat","year":"1988","journal-title":"Prog. Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0361-9230(89)90136-6","article-title":"Intraspinal transplants of serotonergic neurons in the adult rat","volume":"22","author":"Privat","year":"1989","journal-title":"Brain Res. Bull."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/j.pain.0000000000000381","article-title":"Dorsal root ganglion neurons and tyrosine hydroxylase--an intriguing association with implications for sensation and pain","volume":"157","author":"Brumovsky","year":"2016","journal-title":"Pain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0304-3940(02)01256-9","article-title":"Serotonin receptor mRNA expression in rat dorsal root ganglion neurons","volume":"337","author":"Nicholson","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/S0006-8993(98)00360-6","article-title":"The cellular localization of 5-HT2A receptors in the spinal cord and spinal ganglia of the adult rat","volume":"797","author":"Maeshima","year":"1998","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Juric, M., Zeitler, J., Vukojevic, K., Bocina, I., Grobe, M., Kretzschmar, G., Saraga-Babic, M., and Filipovic, N. (2020). Expression of Connexins 37, 43 and 45 in Developing Human Spinal Cord and Ganglia. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249356"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.acthis.2018.08.015","article-title":"Glomeruli from patients with nephrin mutations show increased number of ciliated and poorly differentiated podocytes","volume":"120","author":"Vukojevic","year":"2018","journal-title":"Acta Histochem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kosovic, I., Filipovic, N., Benzon, B., Bocina, I., Glavina Durdov, M., Vukojevic, K., Saraga, M., and Saraga-Babic, M. (2020). Connexin Signaling in the Juxtaglomerular Apparatus (JGA) of Developing, Postnatal Healthy and Nephrotic Human Kidneys. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218349"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:27:25Z","timestamp":1760164045000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,7]]},"references-count":44,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147320"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147320","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,7,7]]}}}