Abstract
Anorectal malformations encompass a broad spectrum of congenital defects and are related to the development of the genital tubercle, including the cloacal plate and urorectal septum. To explore the cellular and molecular basis of anorectal malformations, we analyzed the pathogenetic process using two mouse models: Danforth's short tail (Sd) and all-trans retinoic acid (ATRA)-treated mice. Embryologically, the cloacal plate may be divided into distal and proximal parts, with the distal part subdivided into ventral and dorsal parts. In the two mouse models, anorectal malformations occur due to improper development of the proximal part of the cloacal plate. At 10.5 days postcoitus (dpc), in Sd homozygotes, there was a lack of Shh expression only in the cloacal plate and the endoderm around the cloacal plate. In addition, Wnt5a was not expressed in the mesoderm adjacent to the cloacal plate in the two mouse models, and Axin2, which is regulated by Wnt signaling, was not expressed in the dorsal part of the cloacal plate at 12.5 dpc. Based on these results, we suggest that Wnt5a, which is downstream of Shh signaling, and Axin2 affect the development of the proximal part of the cloacal plate.
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Abbreviations
- ATRA:
-
all-trans retinoic acid
- BrdU:
-
5-bromodeoxyuridine
- dpc:
-
days postcoitus
- d:
-
Danforth's short tail.
References
Hendren WH 1998 Cloaca, the most severe degree of imperforate anus: experience with 195 cases. Ann Surg 228: 331–346
Santulli TV, Schullinger JN, Kiesewetter WB, Bill AH Jr 1971 Imperforate anus: a survey from the members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 6: 484–487
Stevenson R 1993 Human Malformations and Related Anomalies. Oxford University Press, London 493–499
Kluth D, Hillen M, Lambrecht W 1995 The principles of normal and abnormal hindgut development. J Pediatr Surg 30: 1143–1147
Sasaki C, Yamaguchi K, Akita K 2004 Spatiotemporal distribution of apoptosis during normal cloacal development in mice. Anat Rec A Discov Mol Cell Evol Biol 279: 761–767
Fritsch H, Aigner F, Ludwikowski B, Reinstadler-Zankl S, Illig R, Urbas D, Schwarzer C, Longato S 2007 Epithelial and muscular regionalization of the human developing anorectum. Anat Rec (Hoboken) 290: 1449–1458
Ming JE, Roessler E, Muenke M 1998 Human developmental disorders and the Sonic hedgehog pathway. Mol Med Today 4: 343–349
Ingham PW, McMahon AP 2001 Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15: 3059–3087
Ramalho-Santos M, Melton DA, McMahon AP 2000 Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 127: 2763–2772
Mo R, Kim JH, Zhang J, Chiang C, Hui CC, Kim PC 2001 Anorectal malformations caused by defects in sonic hedgehog signaling. Am J Pathol 159: 765–774
Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP 1993 Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417–1430
Goodrich LV, Johnson RL, Milenkovic L, McMahon JA, Scott MP 1996 Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev 10: 301–312
Marigo V, Davey RA, Zuo Y, Cunningham JM, Tabin CJ 1996 Biochemical evidence that patched is the Hedgehog receptor. Nature 384: 176–179
Dolle P, Izpisua-Belmonte JC, Brown JM, Tickle C, Duboule D 1991 HOX-4 genes and the morphogenesis of mammalian genitalia. Genes Dev 5: 1767–1776
Scott V, Morgan EA, Stadler HS 2005 Genitourinary functions of Hoxa13 and Hoxd13. J Biochem 137: 671–676
Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, Innis JW, Holmes LB, Donnenfeld AE, Feingold M, Beemer FA, Hennekam RC, Scambler PJ 2000 Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet 67: 197–202
Warot X, Fromental-Ramain C, Fraulob V, Chambon P, Dolle P 1997 Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development 124: 4781–4791
Perriton CL, Powles N, Chiang C, Maconochie MK, Cohn MJ 2002 Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol 247: 26–46
Yamaguchi TP, Bradley A, McMahon AP, Jones S 1999 A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development 126: 1211–1223
Haraguchi R, Suzuki K, Murakami R, Sakai M, Kamikawa M, Kengaku M, Sekine K, Kawano H, Kato S, Ueno N, Yamada G 2000 Molecular analysis of external genitalia formation: the role of fibroblast growth factor (Fgf) genes during genital tubercle formation. Development 127: 2471–2479
Haraguchi R, Mo R, Hui C, Motoyama J, Makino S, Shiroishi T, Gaffield W, Yamada G 2001 Unique functions of Sonic hedgehog signaling during external genitalia development. Development 128: 4241–4250
Suzuki K, Bachiller D, Chen YP, Kamikawa M, Ogi H, Haraguchi R, Ogino Y, Minami Y, Mishina Y, Ahn K, Crenshaw EB 3rd Yamada G 2003 Regulation of outgrowth and apoptosis for the terminal appendage: external genitalia development by concerted actions of BMP signaling. Development 130: 6209–6220
Paavola LG, Wilson DB, Center EM 1980 Histochemistry of the developing notochord, perichordal sheath and vertebrae in Danforth's short-tail (Sd) and normal C57BL/6 mice. J Embryol Exp Morphol 55: 227–245
Favre A, Briano S, Mazzola C, Brizzolara A, Torre M, Cilli M, Sanguineti M, Martucciello G 1999 Anorectal malformations associated with enteric dysganglionosis in Danforth's short tail (Sd) mice. J Pediatr Surg 34: 1818–1821
Bitoh Y, Shimotake T, Kubota Y, Kimura O, Iwai N 2001 Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations. J Pediatr Surg 36: 377–380
Iulianella A, Beckett B, Petkovich M, Lohnes D 1999 A molecular basis for retinoic acid-induced axial truncation. Dev Biol 205: 33–48
Maden M 2000 The role of retinoic acid in embryonic and post-embryonic development. Proc Nutr Soc 59: 65–73
Kastner P, Mark M, Ghyselinck N, Krezel W, Dupe V, Grondona JM, Chambon P 1997 Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development 124: 313–326
Bellusci S, Furuta Y, Rush MG, Henderson R, Winnier G, Hogan BL 1997 Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis. Development 124: 53–63
Wilkinson DG 1992 In Situ Hybridization: A Practical Approach. Oxford University Press, Oxford 1992
Shum AS, Poon LL, Tang WW, Koide T, Chan BW, Leung YC, Shiroishi T, Copp AJ 1999 Retinoic acid induces down-regulation of Wnt-3a, apoptosis and diversion of tail bud cells to a neural fate in the mouse embryo. Mech Dev 84: 17–30
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F 2002 Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22: 1172–1183
Lin C, Yin Y, Long F, Ma L 2008 Tissue-specific requirements of beta-catenin in genitalia development. Development 135: 2815–2825
Morgan EA, Nguyen SB, Scott V, Stadler HS 2003 Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development 130: 3095–3109
Robertson KE, Tickle C, Darling SM 1997 Shh, Fgf4 and Hoxd gene expression in the mouse limb mutant hypodactyly. Int J Dev Biol 41: 733–736
Blanc E, Roux GL, Benard J, Raguenez G 2005 Low expression of Wnt-5a gene is associated with high-risk neuroblastoma. Oncogene 24: 1277–1283
Saitoh T, Katoh M 2002 Expression and regulation of WNT5A and WNT5B in human cancer: up-regulation of WNT5A by TNFalpha in MKN45 cells and up-regulation of WNT5B by beta-estradiol in MCF-7 cells. Int J Mol Med 10: 345–349
Acknowledgements
We thank Dr. Achim Gossler for kindly providing the Sd mouse.
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Supported by special coordination fund from the Ministry of Education, Science and Sports, Japan.
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Nakata, M., Takada, Y., Hishiki, T. et al. Induction of Wnt5a-Expressing Mesenchymal Cells Adjacent to the Cloacal Plate Is an Essential Process for Its Proximodistal Elongation and Subsequent Anorectal Development. Pediatr Res 66, 149–154 (2009). https://doi.org/10.1203/PDR.0b013e3181aa304a
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DOI: https://doi.org/10.1203/PDR.0b013e3181aa304a
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