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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


  • Koss M
  • Bolze A
  • Brendolan A
  • Saggese M
  • Capellini TD
  • Bojilova E
  • Boisson B
  • Prall OW
  • Elliott DA
  • Solloway M
  • Lenti E
  • Hidaka C
  • Chang CP
  • Mahlaoui N
  • Harvey RP
  • Casanova JL
  • Selleri L


Developmental cell

Publication Data

May 15, 2012

Associated Grants

  • Agency: NIDCR NIH HHS, Id: DE18031
  • Agency: NICHD NIH HHS, Id: HD061403
  • Agency: NICHD NIH HHS, Id: HD43997
  • Agency: NHLBI NIH HHS, Id: HL085345
  • Agency: NICHD NIH HHS, Id: R01 HD061403
  • Agency: NICHD NIH HHS, Id: R01 HD061403-03
  • Agency: NCRR NIH HHS, Id: UL1RR024143

Mesh Terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p15
  • DNA-Binding Proteins
  • Exome
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree
  • Proto-Oncogene Proteins
  • Spleen
  • Splenic Diseases
  • Transcription Factors