Seifert et al. Dev2009

Seifert et al. Dev2009 - RESEARCH ARTICLE 3949 Development...

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3949 RESEARCH ARTICLE INTRODUCTION Mammals develop separate anorectal and urogenital canals by septation of a single posterior sinus known as the cloaca. Anorectal malformations (ARM) frequently occur in association with urogenital anomalies (Saha et al., 2005), suggesting the presence of shared developmental mechanisms. Development of the external genitalia begins at approximately embryonic day (E) 10.5 in the mouse, when a pair of genital swellings emerges anterior to the cloacal membrane (Perriton et al., 2002). Coordinated outgrowth of the genital swellings results in formation of the genital tubercle, the anlagen of the penis and clitoris. The genital tubercle is composed of mesoderm, surface ectoderm and cloacal endoderm that extends into the tubercle to form the urethral plate epithelium. The urethral plate epithelium gives rise to the entire penile urethra (Seifert et al., 2008). Development of the genital tubercle is indistinguishable in male and female embryos until approximately E16, when the urethral plate begins to be masculinized to form the penile urethra, marking the beginning of the hormonally controlled period of sexual differentiation (Seifert et al., 2008). Cloacal septation is initiated at the same stage as external genital development, when mesoderm dorsal to the urachus and ventral to the gut (known as the urorectal septum mesoderm, URSM) begins to accumulate at the anterior end of the cloaca. Mesenchyme of the urorectal septum is flanked by cloacal endoderm on its dorsal, ventral and posterior edges, and expansion of the URSM results in dorsoventral partitioning of the cloaca (Nievelstein et al., 1998; van der Putte, 2005). Disruption of this process can result in congenital anomalies including anogenital fistula and, in more severe cases, persistent cloaca, in which the urethra and/or bladder, reproductive tract and colon converge in a common exterior opening. Persistent cloaca is often associated with hypospadias, a partial or complete failure of urethral tube closure on the ventral side of the phallus. The molecular mechanisms of cloacal septation and genital tubercle formation are not well understood, and even less is known about the basis of associated malformations of these systems. Two members of the Hedgehog (Hh) gene family, Sonic hedgehog ( Shh ) and Indian hedgehog ( Ihh ), are expressed early during anogenital development, and previous work has shown that hedgehog signaling is required for patterning of gastrointestinal organs (Haraguchi et al., 2001; Lipinski et al., 2006; Perriton et al., 2002; Ramalho-Santos et al., 2000; Roberts et al., 1995). Work by a number of labs has shown that Shh is required for outgrowth and patterning of the genital tubercle and for division of the cloaca into separate urogenital and anorectal sinuses. Shh –/– mice have complete agenesis of the external genitalia and persistence of the cloaca (Cheng et al., 2008; Haraguchi et al., 2001; Kim et al., 2001; Kimmel et al., 2000; Mo et
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Seifert et al. Dev2009 - RESEARCH ARTICLE 3949 Development...

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