The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh

A Solanki, CI Lau, JI Saldaña, S Ross… - Journal of Experimental …, 2017 - rupress.org
A Solanki, CI Lau, JI Saldaña, S Ross, T Crompton
Journal of Experimental Medicine, 2017rupress.org
Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in
the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development
was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])–deficient FL
showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use
of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells
and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs …
Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])–deficient FL showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs. RNA sequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL and showed that these cells expressed reduced levels of B-lineage transcription factors and B cell receptor (BCR)/pre-BCR–signaling genes. Expression of the master regulators of B cell development Ebf1 and Pax5 was reduced in developing B cells from Gli3-deficient FL but increased in Shh-deficient FL, and in vitro Shh treatment or neutralization reduced or increased their expression, respectively.
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