Sonic hedgehog controls growth of external genitalia by regulating cell cycle kinetics

Department of Biology, University of Florida, Gainesville, FL 32611, USA.
Nature Communications (Impact Factor: 11.47). 06/2010; 1(3):23. DOI: 10.1038/ncomms1020
Source: PubMed


During embryonic development, cells are instructed which position to occupy, they interpret these cues as differentiation programmes, and expand these patterns by growth. Sonic hedgehog (Shh) specifies positional identity in many organs; however, its role in growth is not well understood. In this study, we show that inactivation of Shh in external genitalia extends the cell cycle from 8.5 to 14.4 h, and genital growth is reduced by ∼75%. Transient Shh signalling establishes pattern in the genital tubercle; however, transcriptional levels of G1 cell cycle regulators are reduced. Consequently, G1 length is extended, leading to fewer progenitor cells entering S-phase. Cell cycle genes responded similarly to Shh inactivation in genitalia and limbs, suggesting that Shh may regulate growth by similar mechanisms in different organ systems. The finding that Shh regulates cell number by controlling the length of specific cell cycle phases identifies a novel mechanism by which Shh elaborates pattern during appendage development.

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Available from: Brandi K Ormerod, Oct 10, 2015
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    • "In addition, Msx2 expression was detected at a site where the urethral epithelium is in contact with the ventral ectoderm at stages 12 and 14 ( fig. 4 P, Q), which corresponds to the region of Bmp4 expression and apoptosis. Although Msx2 expression in the distal genital tubercle is similar to that reported in the mouse, expression along the urethral sulcus occurs in turtles but not in mice [Perriton et al., 2002; Seifert et al., 2010]. Fig. 3 "
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    ABSTRACT: Development of a phallus occurs in almost all amniotes; however, considerable variation in phallus morphology among different amniote lineages has contributed to the debate about their structural homology. Mammals are the only amniotes that form a closed urethral tube within the penis. In contrast, the phallus of reptiles and birds has an open urethral groove, or sulcus spermaticus, that facilitates directional flow of sperm along the penis. One condition of structural homology is that the organs should share a common developmental origin; de novo development from different embryonic progenitors would indicate that the structure re-evolved in a new position. Although a common developmental origin does not itself demonstrate homology, different origins could indicate a lack of homology. To further understand how development of external genitalia evolved in amniotes, we examined this in the turtle Trachemys scripta. We found that phallus development in the turtle closely resembles that of mice at the tissue, cellular, and molecular levels, consistent with the hypothesis that their phalluses are homologous structures. We find that acquisition of specialized characters, such as a closed urethral tube, involved lineage-specific specialization of the common plan for amniote phallus development. © 2014 S. Karger AG, Basel.
    Sexual Development 06/2014; 9(1). DOI:10.1159/000363631 · 2.29 Impact Factor
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    • "eduction of cell cycle proteins , e . g . cyclin E1 ( CCNE1 ) , cyclin B1 ( CCNB1 ) , and cell division cycle 25A ( CDC25A ) [ Seifert et al . , 2010 ] . It suggests that the immature mesenchymal ( progenitor ) cells of mutant GT may spend an extended time in the G1 / G0 phase , thereby limiting the number of cells entering S - and G2/ M - phase [ Seifert et al . , 2010 ] . Over all , it suggests that SHH regulates GT growth by maintaining a supply of mesenchymal cells during GT growth ."
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    ABSTRACT: The study of the external genitalia is divided into 2 developmental stages: the formation and growth of a bipotential genital tubercle (GT) and the sexual differentiation of the male and female GT. The sexually dimorphic processes, which occur during the second part of GT differentiation, are suggested to be governed by androgen signaling and more recently crosstalk with other signaling factors. The process of elucidating the regulatory mechanisms of hormone signaling towards other signaling networks in the GT is still in its early stages. Nevertheless, it is becoming a productive area of research. This review summarizes various studies on the development of the murine GT and the defining characteristics of a masculinized GT and presents the different signaling pathways possibly involved during masculinization. © 2014 S. Karger AG, Basel.
    Sexual Development 02/2014; 8(5). DOI:10.1159/000357932 · 2.29 Impact Factor
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    • "Shh is expressed in the cloacal endoderm and is required for all stages of genitourinary tract development [30], [38], [39]. Shh signaling controls cell cycle kinetics of mesenchyme [42]. It is worth noting that Six6, a homology of Six1, is directly involved in modulating cell cycle of retinal progenitor [43]. "
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    ABSTRACT: Separating digestive and urinary outlets is a critical step during mammalian embryogenesis. However, the natural history of these structures is poorly studied, and little is known about their embryonic origin. Here, we show that peri-cloacal mesenchymal (PCM) progenitors are the major source of these structures. Surprisingly, PCM progenitors also contribute to perineum, a structural barrier separating the urinary and digestive tracts, suggesting a potential role of PCM progenitors in establishing independent urinary and digestive outlets. We demonstrate that Six1 and Six2 are complementarily but asymmetrically expressed in the PCM progenitors. Deletion of these genes results in decreased cell survival and proliferation, and consequently in agenesis of the perineum and severe hypoplasia of the genital tubercle. Together, these findings suggest that PCM progenitors are the unexpected source of perineum and genital tubercle, and establish a basic framework for investigating normal and abnormal development of anorectal and genitourinary structures.
    PLoS ONE 02/2013; 8(2):e55587. DOI:10.1371/journal.pone.0055587 · 3.23 Impact Factor
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