Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh

Marissa L. Gredler, Sara E. Patterson, Ashley W. Seifert, Martin J. Cohn

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the genital tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalDevelopmental Biology
Volume465
Issue number1
DOIs
StatePublished - Sep 1 2020

Bibliographical note

Funding Information:
We thank Emily Merton, Rikesh Patel, Brittany Maillet, Stacey Gray, and Shelby Frantz for assistance and Klaus Kaestner for providing the Foxa1 - and Foxa2 flox mouse lines. M.L.G. was supported by a UF Alumni Fellowship . S.E.P. was supported by a Ruth L. Kirschstein National Research Service Award ( F32 HD062164 ). This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases ( R01-DK110408 ) and the National Institute of Environmental Health Sciences ( R01-ES017099 ) to M.J.C.

Funding Information:
We thank Emily Merton, Rikesh Patel, Brittany Maillet, Stacey Gray, and Shelby Frantz for assistance and Klaus Kaestner for providing the Foxa1- and Foxa2flox mouse lines. M.L.G. was supported by a UF Alumni Fellowship. S.E.P. was supported by a Ruth L. Kirschstein National Research Service Award (F32 HD062164). This study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK110408) and the National Institute of Environmental Health Sciences (R01-ES017099) to M.J.C.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Cloaca
  • External genitalia
  • Foxa1
  • Foxa2
  • Hypospadias
  • Shh
  • Urethra

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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