{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:51:06Z","timestamp":1760151066647,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Science Foundation","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"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to explore how Dab1 gene functional silencing influences the spatial and temporal expression patterns of fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), receptor-interacting protein kinase 5 (RIP5), and huntingtin-interacting protein 2 (HIP2) in the developing and postnatal kidneys of the yotari mice as potential determinants of normal kidney formation and function. Dab1\u2212\/\u2212 animal kidneys exhibit diminished FGFR1\/FGFR2 expression in all examined developmental stages, whereas RIP5 cell immunoreactivity demonstrated negligible variation. The HIP2 expression revealed a discernible difference during the postnatal period, where we noted a significant decrease in almost all the observed kidney structures of yotari animals. An extracellular signal-regulated kinase (Erk1\/2) and mammalian target of rapamycin (mTOR) expression in yotari kidneys decreased in embryonic and postnatal developmental phases for which we can hypothesize that the Erk1\/2 signaling pathway in the yotari mice kidneys is dependent on Reelin with Dab1 only partially implicated in Reelin-mediated MEK\/Erk1\/2 activation. The impairment of FGFR1 and FGFR2 expression suggests the involvement of the observed markers in generating the CAKUT phenotype resulting in renal hypoplasia. Our study demonstrates the critical role of HIP2 in reducing cell death throughout nephrogenesis and maturation in wild-type mice and indicates a possible connection between decreased HIP2 expression in postnatal kidney structures and observed podocyte injury in yotari. Our results emphasize the crucial function of the examined markers throughout normal kidney development and their potential participation in kidney pathology and diagnostics, where they might serve as biomarkers and therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms23042025","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T21:08:43Z","timestamp":1644786523000},"page":"2025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Immunohistochemical Expression Pattern of FGFR1, FGFR2, RIP5, and HIP2 in Developing and Postnatal Kidneys of Dab1\u2212\/\u2212 (yotari) Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6529-5474","authenticated-orcid":false,"given":"Nela","family":"Kelam","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Racetin","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"},{"name":"Department of Medical Genetics, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Katsuyama","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Shiga University of Medical Science, \u00d6tsu 520-2192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2182-2890","authenticated-orcid":false,"given":"Katarina","family":"Vukojevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"},{"name":"Department of Medical Genetics, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Kosti\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0168-0102(97)00088-6","article-title":"A novel neurological mutant mouse, yotari, which exhibits reeler-like phenotype but expresses CR-50 antigen\/reelin","volume":"29","author":"Yoneshima","year":"1997","journal-title":"Neurosci. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Racetin, A., Filipovic, N., Lozic, M., Ogata, M., Gudelj Ensor, L., Kelam, N., Kovacevic, P., Watanabe, K., Katsuyama, Y., and Saraga-Babic, M. (2021). A Homozygous Dab1(-\/-) Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract. Biomolecules, 11.","DOI":"10.3390\/biom11040609"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lozic, M., Filipovic, N., Juric, M., Kosovic, I., Benzon, B., Solic, I., Kelam, N., Racetin, A., Watanabe, K., and Katsuyama, Y. (2021). Alteration of Cx37, Cx40, Cx43, Cx45, Panx1, and Renin Expression Patterns in Postnatal Kidneys of Dab1-\/- (yotari) Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031284"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2484303","DOI":"10.1155\/2017\/2484303","article-title":"Dab1 Contributes to Angiotensin II-Induced Apoptosis via p38 Signaling Pathway in Podocytes","volume":"2017","author":"Gao","year":"2017","journal-title":"BioMed Res. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3325\/cmj.2019.60.521","article-title":"Expression and localization of DAB1 and Reelin during normal human kidney development","volume":"60","author":"Racetin","year":"2019","journal-title":"Croat. Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/39601","article-title":"Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice","volume":"389","author":"Sheldon","year":"1997","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/39607","article-title":"Neuronal position in the developing brain is regulated by mouse disabled-1","volume":"389","author":"Howell","year":"1997","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S31","DOI":"10.1002\/bdra.20778","article-title":"Paper 4: EUROCAT statistical monitoring: Identification and investigation of ten year trends of congenital anomalies in Europe","volume":"91","author":"Loane","year":"2011","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"(1993). Birth Defects Monitoring Program (BDMP)\/Commission on Professional and Hospital Activities (CPHA) surveillance data, 1988\u20131991. Teratology, 48, 658\u2013675.","DOI":"10.1002\/tera.1420480608"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1681\/ASN.2017121265","article-title":"Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract","volume":"29","author":"Connaughton","year":"2018","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1056\/NEJMoa1214479","article-title":"Mutations in DSTYK and dominant urinary tract malformations","volume":"369","author":"Sampogna","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.acthis.2018.01.008","article-title":"Growth factors FGF8 and FGF2 and their receptor FGFR1, transcriptional factors Msx-1 and MSX-2, and apoptotic factors p19 and RIP5 participate in the early human limb development","volume":"120","author":"Becic","year":"2018","journal-title":"Acta Histochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.acthis.2019.04.011","article-title":"Immunohistochemical expression pattern of RIP5, FGFR1, FGFR2 and HIP2 in the normal human kidney development","volume":"121","author":"Racetin","year":"2019","journal-title":"Acta Histochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2684","DOI":"10.1158\/1078-0432.CCR-14-2329","article-title":"Targeting FGFR Signaling in Cancer","volume":"21","author":"Touat","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1007\/s00467-010-1747-z","article-title":"Role of fibroblast growth factor receptor signaling in kidney development","volume":"26","author":"Bates","year":"2011","journal-title":"Pediatr. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The Fibroblast Growth Factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nrc2780","article-title":"Fibroblast growth factor signalling: From development to cancer","volume":"10","author":"Turner","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41392-020-00222-7","article-title":"FGF\/FGFR signaling in health and disease","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1101\/gad.277137.115","article-title":"Genetic insights into the mechanisms of Fgf signaling","volume":"30","author":"Brewer","year":"2016","journal-title":"Genes Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1007\/s00467-015-3151-1","article-title":"Fibroblast growth factor receptor signaling in kidney and lower urinary tract development","volume":"31","author":"Walker","year":"2016","journal-title":"Pediatr. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1161\/HYPERTENSIONAHA.120.15587","article-title":"Endothelial FGFR1 (Fibroblast Growth Factor Receptor 1) Deficiency Contributes Differential Fibrogenic Effects in Kidney and Heart of Diabetic Mice","volume":"76","author":"Li","year":"2020","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Srivastava, S.P., Goodwin, J.E., Tripathi, P., Kanasaki, K., and Koya, D. (2021). Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116027"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1111\/jdi.13219","article-title":"N-acetyl-seryl-aspartyl-lysyl-proline is a valuable endogenous antifibrotic peptide for kidney fibrosis in diabetes: An update and translational aspects","volume":"11","author":"Kanasaki","year":"2020","journal-title":"J. Diabetes Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"696475","DOI":"10.1155\/2014\/696475","article-title":"N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition","volume":"2014","author":"Nagai","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2965","DOI":"10.1038\/cddis.2017.353","article-title":"FGFR1 is critical for the anti-endothelial mesenchymal transition effect of N-acetyl-seryl-aspartyl-lysyl-proline via induction of the MAP4K4 pathway","volume":"8","author":"Li","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.ydbio.2004.09.002","article-title":"Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud","volume":"276","author":"Zhao","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1681\/ASN.2009050532","article-title":"Three-dimensional imaging reveals ureteric and mesenchymal defects in Fgfr2-mutant kidneys","volume":"20","author":"Argyropoulos","year":"2009","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/dvdy.22501","article-title":"Fgfr1 and the IIIc isoform of Fgfr2 play critical roles in the metanephric mesenchyme mediating early inductive events in kidney development","volume":"240","author":"Cusack","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1203\/PDR.0b013e318187cc12","article-title":"Role of fibroblast growth factor receptor 2 in kidney mesenchyme","volume":"64","author":"Hains","year":"2008","journal-title":"Pediatr. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1016\/j.juro.2009.12.095","article-title":"High incidence of vesicoureteral reflux in mice with Fgfr2 deletion in kidney mesenchyma","volume":"183","author":"Hains","year":"2010","journal-title":"J. Urol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5082","DOI":"10.1073\/pnas.95.9.5082","article-title":"Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development","volume":"95","author":"Arman","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1242\/dev.125.4.753","article-title":"Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction","volume":"125","author":"Xu","year":"1998","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1101\/gad.8.24.3032","article-title":"fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation","volume":"8","author":"Yamaguchi","year":"1994","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1101\/gad.8.24.3045","article-title":"Murine FGFR-1 is required for early postimplantation growth and axial organization","volume":"8","author":"Deng","year":"1994","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1203\/01.pdr.0000202764.02295.45","article-title":"Link between reduced nephron number and hypertension: Studies in a mutant mouse model","volume":"59","author":"Poladia","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1093\/emboj\/17.6.1642","article-title":"Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning","volume":"17","author":"Celli","year":"1998","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"F888","DOI":"10.1152\/ajprenal.00624.2014","article-title":"Fgfr2 is integral for bladder mesenchyme patterning and function","volume":"308","author":"Walker","year":"2015","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ydbio.2005.12.034","article-title":"Role of fibroblast growth factor receptors 1 and 2 in the metanephric mesenchyme","volume":"291","author":"Poladia","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1002\/ajmg.1320450618","article-title":"Visceral anomalies in the Apert syndrome","volume":"45","author":"Cohen","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/S0344-0338(97)80018-0","article-title":"A 19-week-old fetus with craniosynostosis, renal agenesis and gastroschisis: Case report and differential diagnosis","volume":"193","author":"Sergi","year":"1997","journal-title":"Pathol. Res. Pract."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/(SICI)1098-1004(1999)14:2<115::AID-HUMU3>3.0.CO;2-2","article-title":"Clinical spectrum of fibroblast growth factor receptor mutations","volume":"14","author":"Wilcox","year":"1999","journal-title":"Hum. Mutat."},{"key":"ref_42","first-page":"200","article-title":"High-grade vesicoureteral reflux in Pfeiffer syndrome","volume":"5","author":"Seyedzadeh","year":"2008","journal-title":"Urol. J."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Pastar, V., Lozic, M., Kelam, N., Filipovic, N., Bernard, B., Katsuyama, Y., and Vukojevic, K. (2021). Connexin Expression Is Altered in Liver Development of Yotari (dab1 -\/-) Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910712"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e47673","DOI":"10.7554\/eLife.47673","article-title":"N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration","volume":"8","author":"Kon","year":"2019","journal-title":"Elife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1471-4159.2004.03007.x","article-title":"Multiple pathways of apolipoprotein E signaling in primary neurons","volume":"93","author":"Hoe","year":"2005","journal-title":"J. Neurochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"20307","DOI":"10.1074\/jbc.M114.576249","article-title":"Reelin induces Erk1\/2 signaling in cortical neurons through a non-canonical pathway","volume":"289","author":"Lee","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1128\/MCB.00928-07","article-title":"Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulate dendritic growth","volume":"27","author":"Jossin","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.bbrc.2004.04.194","article-title":"RIP5 is a RIP-homologous inducer of cell death","volume":"319","author":"Zha","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41419-018-1066-z","article-title":"Reduction of HIP2 expression causes motor function impairment and increased vulnerability to dopaminergic degeneration in Parkinson\u2019s disease models","volume":"9","author":"Su","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"774","DOI":"10.21037\/tcr.2019.12.12","article-title":"Reduction of Hip2 suppresses gastric cancer cell proliferation, migration, invasion and tumorigenesis","volume":"9","author":"Wu","year":"2020","journal-title":"Transl. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1093\/cercor\/bhv334","article-title":"Dorsal Forebrain-Specific Deficiency of Reelin-Dab1 Signal Causes Behavioral Abnormalities Related to Psychiatric Disorders","volume":"27","author":"Imai","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1037\/1040-3590.6.4.284","article-title":"Guidelines, Criteria, and Rules of Thumb for Evaluating Normed and Standardized Assessment Instrument in Psychology","volume":"6","author":"Cicchetti","year":"1994","journal-title":"Psychol. Assess."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:17:58Z","timestamp":1760134678000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,11]]},"references-count":52,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23042025"],"URL":"https:\/\/doi.org\/10.3390\/ijms23042025","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,2,11]]}}}