Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

Matthew Koss, Alexandra Bolze, Andrea Brendolan, Matilde Saggese, Terence D Capellini, Ekaterina Bojilova, Bertrand Bolsson, Owen WJ Prall, David A Elliott, Mark J Solloway, Elisa Lenti, Chisa Hidaka, Ching-Pin Chang, Nizar Mazhlaoui, Richard P Harvey, Jean-Laurent Casanova, Licia Selleri

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    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.
    Original languageEnglish
    Pages (from-to)913 - 926
    Number of pages14
    JournalDevelopmental Cell
    Issue number5
    Publication statusPublished - 2012

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