Sall1 regulates microtubule acetylation in mesenchymal cells during mouse urethral development.

Male embryonic external genitalia (eExG) undergo sexually dimorphic urethral development in response to androgen signaling (urethral masculinization). Whereas androgen is an essential masculinization factor for eExG, the specific molecular and cellular mechanisms are still unclear. Sall1 is a transcription factor that has been linked to the congenital disease Townes-Brocks syndrome, which includes anorectal and urogenital malformations. Currently, the functional role of Sall1 for normal urethral development is still unclear. In this study, we show that Sall1 is required to regulate proper microtubule acetylation to facilitate mesenchymal cell migration during urethral masculinization of mouse eExG. Mutant male mice with loss of function of mesenchymal Sall1 exhibited severe urethral defects, without prominent alteration of androgen signaling. Loss of Sall1 induced hyperacetylated microtubules in the eExG mesenchyme. Microtubule hyperacetylation resulted in defective fibrillar adhesions and fibronectin expression which impaired cell migration. Our findings reveal a novel mechanism of Sall1-regulated mesenchymal cell migration for urethral development. This mechanism for Sall1 may underlie the etiology of diseases such as Townes-Brocks syndrome.