TY - JOUR
T1 - Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module
AU - Koss, Matthew
AU - Bolze, Alexandra
AU - Brendolan, Andrea
AU - Saggese, Matilde
AU - Capellini, Terence D
AU - Bojilova, Ekaterina
AU - Bolsson, Bertrand
AU - Prall, Owen WJ
AU - Elliott, David A
AU - Solloway, Mark J
AU - Lenti, Elisa
AU - Hidaka, Chisa
AU - Chang, Ching-Pin
AU - Mazhlaoui, Nizar
AU - Harvey, Richard P
AU - Casanova, Jean-Laurent
AU - Selleri, Licia
PY - 2012
Y1 - 2012
N2 - The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.
AB - The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.
UR - http://www.sciencedirect.com/science/article/pii/S1534580712000901
U2 - 10.1016/j.devcel.2012.02.009
DO - 10.1016/j.devcel.2012.02.009
M3 - Article
VL - 22
SP - 913
EP - 926
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 5
ER -