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Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments
Open AccessArticle

Discrete Hedgehog Factor Expression and Action in the Developing Phallus

School of BioSciences, The University of Melbourne, Parkville, VIC 3010, Australia
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1237;
Received: 8 January 2020 / Revised: 10 February 2020 / Accepted: 10 February 2020 / Published: 12 February 2020
(This article belongs to the Special Issue Hedgehog Signaling in Organogenesis and Tumor Microenvironment)
Hypospadias is a failure of urethral closure within the penis occurring in 1 in 125 boys at birth and is increasing in frequency. While paracrine hedgehog signalling is implicated in the process of urethral closure, how these factors act on a tissue level to execute closure itself is unknown. This study aimed to understand the role of different hedgehog signalling members in urethral closure. The tammar wallaby (Macropus eugenii) provides a unique system to understand urethral closure as it allows direct treatment of developing offspring because mothers give birth to young before urethral closure begins. Wallaby pouch young were treated with vehicle or oestradiol (known to induce hypospadias in males) and samples subjected to RNAseq for differential expression and gene ontology analyses. Localisation of Sonic Hedgehog (SHH) and Indian Hedgehog (IHH), as well as the transcription factor SOX9, were assessed in normal phallus tissue using immunofluorescence. Normal tissue culture explants were treated with SHH or IHH and analysed for AR, ESR1, PTCH1, GLI2, SOX9, IHH and SHH expression by qPCR. Gene ontology analysis showed enrichment for bone differentiation terms in male samples compared with either female samples or males treated with oestradiol. Expression of SHH and IHH localised to specific tissue areas during development, akin to their compartmentalised expression in developing bone. Treatment of phallus explants with SHH or IHH induced factor-specific expression of genes associated with bone differentiation. This reveals a potential developmental interaction involved in urethral closure that mimics bone differentiation and incorporates discrete hedgehog activity within the developing phallus and phallic urethra. View Full-Text
Keywords: hypospadias; urethra; penis; bone; hedgehog signalling hypospadias; urethra; penis; bone; hedgehog signalling
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Tarulli, G.A.; Pask, A.J.; Renfree, M.B. Discrete Hedgehog Factor Expression and Action in the Developing Phallus. Int. J. Mol. Sci. 2020, 21, 1237.

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