{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:31:34Z","timestamp":1760401894854,"version":"build-2065373602"},"reference-count":100,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T00:00:00Z","timestamp":1579132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Congenital anomalies in phalluses caused by endocrine disruptors have gained a great deal of attention due to its annual increasing rate in males. However, the endocrine-driven molecular regulatory mechanism of abnormal phallus development is complex and remains largely unknown. Here, we review the direct effect of androgen and oestrogen on molecular regulation in phalluses using the marsupial tammar wallaby, whose phallus differentiation occurs after birth. We summarize and discuss the molecular mechanisms underlying phallus differentiation mediated by sonic hedgehog (SHH) at day 50 pp and phallus elongation mediated by insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3), as well as multiple phallus-regulating genes expressed after day 50 pp. We also identify hormone-responsive long non-coding RNAs (lncRNAs) that are co-expressed with their neighboring coding genes. We show that the activation of SHH and IGF1, mediated by balanced androgen receptor (AR) and estrogen receptor 1 (ESR1) signalling, initiates a complex regulatory network in males to constrain the timing of phallus differentiation and to activate the downstream genes that maintain urethral closure and phallus elongation at later stages.<\/jats:p>","DOI":"10.3390\/genes11010106","type":"journal-article","created":{"date-parts":[[2020,1,17]],"date-time":"2020-01-17T07:39:02Z","timestamp":1579246742000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hormonal and Molecular Regulation of Phallus Differentiation in a Marsupial Tammar Wallaby"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-0788","authenticated-orcid":false,"given":"Yu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32603, USA"},{"name":"School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-0436","authenticated-orcid":false,"given":"Marilyn B.","family":"Renfree","sequence":"additional","affiliation":[{"name":"School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1071\/ZO05057","article-title":"Sexual development of a model marsupial male","volume":"54","author":"Renfree","year":"2006","journal-title":"Aust. J. Zool."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/BF00195006","article-title":"Sexual differentiation of the urogenital system of the fetal and neonatal tammar wallaby, Macropus eugenii","volume":"194","author":"Renfree","year":"1996","journal-title":"Anat. Embryol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000334053","article-title":"Development of the penile urethra in the tammar wallaby","volume":"5","author":"Leihy","year":"2011","journal-title":"Sex. Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s004290050243","article-title":"Development of the penis and clitoris in the tammar wallaby, Macropus eugenii","volume":"199","author":"Butler","year":"1999","journal-title":"Anat. Embryol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1210\/en.2004-0150","article-title":"Penile development is initiated in the tammar wallaby pouch young during the period when 5\u03b1-androstane-3\u03b1, 17\u03b2-diol is secreted by the testes","volume":"145","author":"Leihy","year":"2004","journal-title":"Endocrinology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.diff.2013.11.003","article-title":"Inducing sex reversal of the urogenital system of marsupials","volume":"87","author":"Renfree","year":"2014","journal-title":"Differentiation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1095\/biolreprod47.4.644","article-title":"Steroid hormone content of the gonads of the tammar wallaby during sexual differentiation","volume":"47","author":"Renfree","year":"1992","journal-title":"Biol. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1095\/biolreprod61.2.471","article-title":"Virilization of the male pouch young of the tammar wallaby does not appear to be mediated by plasma testosterone or dihydrotestosterone","volume":"61","author":"Wilson","year":"1999","journal-title":"Biol. Reprod."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1159\/000357927","article-title":"A dual role for SHH during phallus development in a marsupial","volume":"8","author":"Chew","year":"2014","journal-title":"Sex. Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1172\/JCI34241","article-title":"Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism","volume":"118","author":"Welsh","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000363609","article-title":"The masculinization programming window","volume":"27","author":"Welsh","year":"2014","journal-title":"Endocr. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e144","DOI":"10.1111\/j.1365-2605.2009.00978.x","article-title":"Critical androgen-sensitive periods of rat penis and clitoris development","volume":"33","author":"Welsh","year":"2010","journal-title":"Int. J. Androl."},{"key":"ref_13","first-page":"806","article-title":"Hormone-responsive genes in the SHH and WNT\/\u03b2-catenin signaling pathways influence urethral closure and phallus growth","volume":"99","author":"Chen","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1002\/ijc.27384","article-title":"Androgens regulate hedgehog signalling and proliferation in androgen-dependent prostate cells","volume":"131","author":"Sirab","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/REP-18-0416","article-title":"Effects of androgen and oestrogen on the IGF pathways controlling phallus growth","volume":"157","author":"Chen","year":"2019","journal-title":"Reproduction"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.mce.2011.10.016","article-title":"Maturation of the growth axis in marsupials occurs gradually during post-natal life and over an equivalent developmental stage relative to eutherian species","volume":"349","author":"Menzies","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1210\/me.2008-0478","article-title":"Genetic interactions of the androgen and Wnt\/\u03b2-catenin pathways for the masculinization of external genitalia","volume":"23","author":"Miyagawa","year":"2009","journal-title":"Mol. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1242\/dev.039438","article-title":"Dosage-dependent hedgehog signals integrated with Wnt\/\u03b2-catenin signaling regulate external genitalia formation as an appendicular program","volume":"136","author":"Miyagawa","year":"2009","journal-title":"Development"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/ncomms1020","article-title":"Sonic hedgehog controls growth of external genitalia by regulating cell cycle kinetics","volume":"1","author":"Seifert","year":"2010","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1242\/jcs.00623","article-title":"Secreted antagonists of the Wnt signalling pathway","volume":"116","author":"Kawano","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/18899","article-title":"A new secreted protein that binds to Wnt proteins and inhibits their activites","volume":"398","author":"Hsieh","year":"1999","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/cdd.2014.20","article-title":"Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant wnt-\u03b2-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations","volume":"21","author":"Ng","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16407","DOI":"10.1073\/pnas.1413273111","article-title":"Sexually dimorphic expression of Mafb regulates masculinization of the embryonic urethral formation","volume":"111","author":"Suzuki","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1210\/en.2015-1586","article-title":"Androgen regulates Mafb expression through its 3\u2019 UTR during mouse urethral masculinization","volume":"157","author":"Matsushita","year":"2015","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41585-018-0008-y","article-title":"Regulation of masculinization: Androgen signalling for external genitalia development","volume":"15","author":"Matsushita","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4867","DOI":"10.1242\/dev.124.23.4867","article-title":"Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung","volume":"124","author":"Bellusci","year":"1997","journal-title":"Development"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1242\/dev.127.11.2471","article-title":"Molecular analysis of external genitalia formation: The role of fibroblast growth factor (FGF) genes during genital tubercle formation","volume":"127","author":"Haraguchi","year":"2000","journal-title":"Development"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1242\/dev.01778","article-title":"Development of the mammalian urethra is controlled by Fgfr2-IIIb","volume":"132","author":"Petiot","year":"2005","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s00429-004-0419-9","article-title":"Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors","volume":"208","author":"Satoh","year":"2004","journal-title":"Anat. Embryol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"12256","DOI":"10.1073\/pnas.220412297","article-title":"Prostate formation in a marsupial is mediated by the testicular androgen 5\u03b1-androstane-3\u03b1, 17\u03b2-diol","volume":"97","author":"Shaw","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1242\/dev.104.4.689","article-title":"Experimental manipulation of sexual differentiation in wallaby pouch young treated with exogenous steroids","volume":"104","author":"Shaw","year":"1988","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1046\/j.1432-0436.1999.6420115.x","article-title":"Ontogeny of the male urethra: Theory of endodermal differentiation","volume":"64","author":"Kurzrock","year":"1999","journal-title":"Differentiation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1046\/j.1464-410X.1997.00119.x","article-title":"Neuroanatomical ontogeny of the human fetal penis","volume":"79","author":"Baskin","year":"1997","journal-title":"Br. J. Urol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.diff.2018.08.001","article-title":"Development of the human penis and clitoris","volume":"103","author":"Baskin","year":"2018","journal-title":"Differentiation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/aja.1000130303","article-title":"The development of the human prostate gland with reference to the development of other structures at the neck of the urinary bladder","volume":"13","author":"Lowsley","year":"1912","journal-title":"Am. J. Anat."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/ar.1091960302","article-title":"Correlation of early cytodifferentiation of the human fetal prostate and leydig cells","volume":"196","author":"Santti","year":"1980","journal-title":"Anat. Rec."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1006\/dbio.2002.0668","article-title":"Sonic hedgehog signaling from the urethral epithelium controls external genital development","volume":"247","author":"Perriton","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4241","DOI":"10.1242\/dev.128.21.4241","article-title":"Unique functions of sonic hedgehog signaling during external genitalia development","volume":"128","author":"Haraguchi","year":"2001","journal-title":"Development"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.diff.2018.05.001","article-title":"Contrasting mechanisms of penile urethral formation in mouse and human","volume":"101","author":"Liu","year":"2018","journal-title":"Differentiation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1210\/edrv-8-3-338","article-title":"The endocrinology and developmental biology of the prostate","volume":"8","author":"Cunha","year":"1987","journal-title":"Endocr. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/S0022-5347(17)35273-4","article-title":"Ductal budding and branching patterns in the developing prostate","volume":"151","author":"Timms","year":"1994","journal-title":"J. Urol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/aja.1000600105","article-title":"Normal development of the prostate and seminal vesicles of the rat with a study of experimental postnatal modifications","volume":"60","author":"Price","year":"1936","journal-title":"Am. J. Anat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1538\/expanim1978.34.4_439","article-title":"Development of the external genitalia in rat fetuses","volume":"34","author":"Inomata","year":"1985","journal-title":"Exp. Anim."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1159\/000274458","article-title":"Differential modulation of sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network","volume":"32","author":"Fernandez","year":"2010","journal-title":"Dev. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6156","DOI":"10.1038\/sj.onc.1207818","article-title":"Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice","volume":"23","author":"Rao","year":"2004","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1006\/dbio.2000.9784","article-title":"IGFs, insulin, Shh, bFGF, and TFG-\u03b21 interact synergistically to promote somite myogenesis in vitro","volume":"224","author":"Pirskanen","year":"2000","journal-title":"Dev. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Andersen, M., N\u00f8rgaard-Pedersen, D., Brandt, J., Pettersson, I., and Slaaby, R. (2017). IGF1 and IGF2 specificities to the two insulin receptor isoforms are determined by insulin receptor amino acid 718. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178885"},{"key":"ref_48","first-page":"152","article-title":"Genetic pituitary dwarfism with high serum concentation of growth hormone\u2014A new inborn error of metabolism?","volume":"2","author":"Laron","year":"1966","journal-title":"Isr. J. Med. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1530\/eje.0.1380176","article-title":"Effect of insulin-like growth factor-I treatment on serum androgens and testicular and penile size in males with Laron syndrome (primary growth hormone resistance)","volume":"138","author":"Laron","year":"1998","journal-title":"Eur. J. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S0022-5347(01)66003-8","article-title":"Micropenis secondary to growth hormone deficiency: Does treatment with growth hormone alone result in adequate penile growth?","volume":"156","author":"Levy","year":"1996","journal-title":"J. Urol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1210\/endo.133.3.7689959","article-title":"Potentiation of insulin-like growth factor-I (IGF-I) activity by an antibody: Supportive evidence for enhancement of IGF-I bioavailability in vivo by IGF binding proteins","volume":"133","author":"Stewart","year":"1993","journal-title":"Endocrinology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6558","DOI":"10.1093\/emboj\/17.22.6558","article-title":"Structure of the IGF-binding domain of the insulin-like growth factor-binding protein-5 (IGFBP-5): Implications for IGF and IGF-I receptor interactions","volume":"17","author":"Kalus","year":"1998","journal-title":"EMBO J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.tem.2016.03.019","article-title":"Role of IGF binding proteins in regulating metabolism","volume":"27","author":"Clemmons","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/jcp.20000","article-title":"IGF-I mRNA levels in bovine satellite cell cultures: Effects of fusion and anabolic steroid treatment","volume":"201","author":"Pampusch","year":"2004","journal-title":"J. Cell. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0960-0760(94)90115-5","article-title":"Androgen regulation of the insulin-like growth factor-I and the estrogen receptor in rat uterus and liver","volume":"51","author":"Sahlin","year":"1994","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"E573","DOI":"10.1152\/ajpendo.00454.2004","article-title":"Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells","volume":"288","author":"Arnold","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E952","DOI":"10.1152\/ajpendo.00451.2005","article-title":"DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells","volume":"290","author":"Le","year":"2006","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1096\/fsb2fj000398com","article-title":"Estrogen augments glucose transporter and IGF1 expression in primate cerebral cortex","volume":"15","author":"Cheng","year":"2001","journal-title":"FASEB J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.1074\/jbc.M109.043471","article-title":"Estrogen-mediated regulation of IGF1 transcription and uterine growth involves direct binding of estrogen receptor \u03b1 to estrogen-responsive elements","volume":"285","author":"Hewitt","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1677\/joe.1.06862","article-title":"Region-specific expression of androgen and growth factor pathway genes in the rat epididymis and the effects of dual 5\u03b1-reductase inhibition","volume":"190","author":"Henderson","year":"2006","journal-title":"J. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/sj.bjc.6602520","article-title":"Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: Implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer","volume":"92","author":"Koike","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1002\/pros.20420","article-title":"Differential regulation of IGFBP-3 by the androgen receptor in the lineage-related androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer models","volume":"66","author":"Kojima","year":"2006","journal-title":"Prostate"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/ijc.23100","article-title":"The role of insulin-like growth factor binding protein-3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells","volume":"122","author":"Peng","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1097-4652(200004)183:1<1::AID-JCP1>3.0.CO;2-J","article-title":"Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis","volume":"183","author":"Grimberg","year":"2000","journal-title":"J. Cell. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1016\/S0959-8049(00)00102-7","article-title":"Insulin-like growth factor physiology and cancer risk","volume":"36","author":"Pollak","year":"2000","journal-title":"Eur. J. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ygcen.2004.12.022","article-title":"Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions","volume":"142","author":"Duan","year":"2005","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/0006-291X(91)91410-E","article-title":"Intact but not truncated insulin-like growth factor binding protein-3 (IGFBP-3) blocks IGF I-induced stimulation of osteoblasts: Control of IGF signalling to bone cells by IGFBP-3-specific proteolysis?","volume":"179","author":"Schmid","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_68","first-page":"361","article-title":"The human insulin-like growth factor (IGF) binding protein-3 inhibits the growth of fibroblasts with a targeted disruption of the Igf-1 receptor gene","volume":"9","author":"Valentinis","year":"1995","journal-title":"Mol. Endocrinol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"16433","DOI":"10.1016\/S0021-9258(17)34025-5","article-title":"Estrogen regulation of the insulin-like growth factor 1 gene transcription involves an AP-1 enhancer","volume":"269","author":"Umayahara","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/0306-4522(96)00219-9","article-title":"Androgens selectively modulate C-Fos messenger RNA induction in the rat hippocampus following novelty","volume":"74","author":"Kerr","year":"1996","journal-title":"Neuroscience"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/S0022-5347(05)00651-8","article-title":"The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer","volume":"175","author":"Pelzer","year":"2006","journal-title":"J. Urol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0304-419X(91)90011-9","article-title":"The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation","volume":"1072","author":"Angel","year":"1991","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ydbio.2008.03.017","article-title":"Cell lineage analysis demonstrates an endodermal origin of the distal urethra and perineum","volume":"318","author":"Seifert","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1242\/dev.042291","article-title":"Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development","volume":"136","author":"Seifert","year":"2009","journal-title":"Development"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.diff.2019.08.004","article-title":"Regulatory roles of epithelial-mesenchymal interaction (EMI) during early and androgen dependent external genitalia development","volume":"110","author":"Hyuga","year":"2019","journal-title":"Differentiation"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ydbio.2004.03.027","article-title":"Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development","volume":"271","author":"Dravis","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1242\/dev.119891","article-title":"Tissue-specific roles of Fgfr2 in development of the external genitalia","volume":"142","author":"Gredler","year":"2015","journal-title":"Development"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/dvdy.24277","article-title":"Tissue-specific roles of FGF signaling in external genitalia development","volume":"244","author":"Harada","year":"2015","journal-title":"Dev. Dyn."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5109","DOI":"10.1242\/dev.128.24.5109","article-title":"Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis","volume":"128","author":"Bhushan","year":"2001","journal-title":"Development"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/dvdy.10368","article-title":"Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells","volume":"228","author":"Hart","year":"2003","journal-title":"Dev. Dyn."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1242\/dev.01690","article-title":"Fgfr2b signaling regulates ex vivo submandibular gland epithelial cell proliferation and branching morphogenesis","volume":"132","author":"Steinberg","year":"2005","journal-title":"Development"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1111\/j.1440-169X.2009.01140.x","article-title":"Mammary epithelial-specific knockout of the ephrin-B2 gene leads to precocious epithelial cell death at lactation","volume":"51","author":"Weiler","year":"2009","journal-title":"Dev. Growth Differ."},{"key":"ref_83","first-page":"335","article-title":"Dlx5 regulates chondrocyte differentiation at multiple stages","volume":"47","author":"Bendall","year":"2003","journal-title":"Int. J. Dev. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1159\/000445661","article-title":"Transcription factor MafB promotes hepatocellular carcinoma cell proliferation through up-regulation of cyclin D1","volume":"39","author":"Yu","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1038\/sj.onc.1204383","article-title":"Ap-1 in cell proliferation and survival","volume":"20","author":"Shaulian","year":"2001","journal-title":"Oncogene"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.tcb.2007.03.004","article-title":"Bidirectional Eph\u2013ephrin signaling during axon guidance","volume":"17","author":"Egea","year":"2007","journal-title":"Trends Cell Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/sj.ejhg.5201925","article-title":"Abnormal urethra formation in mouse models of split-hand\/split-foot malformation type 1 and type 4","volume":"16","author":"Suzuki","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Chen, Y., Kuroki, Y., Shaw, G., Pask, A.J., Yu, H., Toyoda, A., Fujiyama, A., and Renfree, M.B. (2019). Androgen and oestrogen affect the expression of long non-coding rnas during phallus development in a marsupial. Non-Coding RNA, 5.","DOI":"10.3390\/ncrna5010003"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"T87","DOI":"10.1530\/JME-17-0284","article-title":"Role of IGF-I and EFN-EPH signaling in skeletal metabolism","volume":"61","author":"Lindsey","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"625","DOI":"10.2478\/s11536-011-0054-9","article-title":"A new case of rare proximal 3q13 interstitial deletion","volume":"6","author":"Lovrecic","year":"2011","journal-title":"Open Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.ejmg.2012.10.004","article-title":"Acrocallosal syndrome: Identification of a novel KIF7 mutation and evidence for oligogenic inheritance","volume":"56","author":"Walsh","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.gene.2013.01.055","article-title":"Prenatal diagnosis of ring chromosome 2 with lissencephaly and 2p25.3 and 2q37.3 microdeletions detected using array comparative genomic hybridization","volume":"519","author":"Chen","year":"2013","journal-title":"Gene"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"E7194","DOI":"10.1073\/pnas.1515981112","article-title":"Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies","volume":"112","author":"Zheng","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"fj-201802586RR","DOI":"10.1096\/fj.201802586RR","article-title":"A critical role for estrogen signaling in penis development","volume":"33","author":"Govers","year":"2019","journal-title":"FASEB J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"11452","DOI":"10.1073\/pnas.1106083108","article-title":"R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt\/\u03b2-catenin signaling","volume":"108","author":"Carmon","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"E1221","DOI":"10.1073\/pnas.1323106111","article-title":"RSPO\u2013LGR4 functions via IQGAP1 to potentiate Wnt signaling","volume":"111","author":"Carmon","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1101\/gad.219915.113","article-title":"The structural basis of R-spondin recognition by LGR5 and RNF43","volume":"27","author":"Chen","year":"2013","journal-title":"Genes Dev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"23","DOI":"10.4161\/cc.5.1.2305","article-title":"R-Spondin proteins: A novel link to \u03b2-catenin activation","volume":"5","author":"Kim","year":"2006","journal-title":"Cell Cycle"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/ajmg.10271","article-title":"Absence of thumbs, A\/hypoplasia of radius, hypoplasia of ulnae, retarded bone age, short stature, microcephaly, hypoplastic genitalia, and mental retardation","volume":"108","author":"Wieczorek","year":"2002","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1136\/jmg.2008.059451","article-title":"Biallelic loss of function of the promyelocytic leukaemia zinc finger (PLZF) gene causes severe skeletal defects and genital hypoplasia","volume":"45","author":"Fischer","year":"2008","journal-title":"J. Med. 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