Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module.
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.
Pubmed ID: 22560297 RIS Download
Adolescent | Amino Acid Sequence | Animals | Cells, Cultured | Cyclin-Dependent Kinase Inhibitor p15 | DNA-Binding Proteins | Exome | Female | Gene Expression Profiling | Gene Expression Regulation, Developmental | Homeobox Protein Nkx-2.5 | Homeodomain Proteins | Humans | Infant | Male | Mice | Mice, Transgenic | Molecular Sequence Data | Mutation, Missense | Pedigree | Proto-Oncogene Proteins | Spleen | Splenic Diseases | Transcription Factors