Congenital Asplenia in Mice and Humans with Mutations in a Pbx/Nkx2-5/p15 Module

Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
Developmental Cell (Impact Factor: 10.37). 05/2012; 22(5):913-26. DOI: 10.1016/j.devcel.2012.02.009
Source: PubMed

ABSTRACT 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.

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