10.1371/journal.pgen.1006138
Shinichi Hayashi
Shinichi
Hayashi
Ryutaro Akiyama
Ryutaro
Akiyama
Julia Wong
Julia
Wong
Naoyuki Tahara
Naoyuki
Tahara
Hiroko Kawakami
Hiroko
Kawakami
Yasuhiko Kawakami
Yasuhiko
Kawakami
<i>Gata6</i>-Dependent GLI3 Repressor Function is Essential in Anterior Limb Progenitor Cells for Proper Limb Development
Public Library of Science
2016
Proper Limb Development Gli 3
Dependent GLI 3 Repressor Function
ectopic
Gli 3 function
bud
Gata 6 represses
Gata 6
Gli 3 repressor function
GLI 3R
GATA transcription factor family
Hedgehog
limb development
Anterior Limb Progenitor Cells
Tcre deleter causes preaxial polydactyly
limb progenitor cells
GLI 3R activities
novel mechanism
expression
2016-06-28 18:46:44
Dataset
https://plos.figshare.com/articles/dataset/_i_Gata6_i_-Dependent_GLI3_Repressor_Function_is_Essential_in_Anterior_Limb_Progenitor_Cells_for_Proper_Limb_Development/3921507
<div><p><i>Gli3</i> is a major regulator of Hedgehog signaling during limb development. In the anterior mesenchyme, GLI3 is proteolytically processed into GLI3R, a truncated repressor form that inhibits Hedgehog signaling. Although numerous studies have identified mechanisms that regulate <i>Gli3</i> function in vitro, it is not completely understood how <i>Gli3</i> function is regulated in vivo. In this study, we show a novel mechanism of regulation of GLI3R activities in limb buds by <i>Gata6</i>, a member of the GATA transcription factor family. We show that conditional inactivation of <i>Gata6</i> prior to limb outgrowth by the <i>Tcre</i> deleter causes preaxial polydactyly, the formation of an anterior extra digit, in hindlimbs. A recent study suggested that <i>Gata6</i> represses <i>Shh</i> transcription in hindlimb buds. However, we found that ectopic Hedgehog signaling precedes ectopic <i>Shh</i> expression. In conjunction, we observed <i>Gata6</i> and <i>Gli3</i> genetically interact, and compound heterozygous mutants develop preaxial polydactyly without ectopic <i>Shh</i> expression, indicating an additional prior mechanism to prevent polydactyly. These results support the idea that <i>Gata6</i> possesses dual roles during limb development: enhancement of <i>Gli3</i> repressor function to repress Hedgehog signaling in the anterior limb bud, and negative regulation of <i>Shh</i> expression. Our in vitro and in vivo studies identified that GATA6 physically interacts with GLI3R to facilitate nuclear localization of GLI3R and repressor activities of GLI3R. Both the genetic and biochemical data elucidates a novel mechanism by <i>Gata6</i> to regulate GLI3R activities in the anterior limb progenitor cells to prevent polydactyly and attain proper development of the mammalian autopod.</p></div>