2. Academic Validation
  3. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

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

  • Dev Cell. 2012 May 15;22(5):913-26. doi: 10.1016/j.devcel.2012.02.009.
Matthew Koss 1,  Alexandre Bolze,  Andrea Brendolan,  Matilde Saggese,  Terence D Capellini,  Ekaterina Bojilova,  Bertrand Boisson,  Owen W J Prall,  David A Elliott,  Mark Solloway,  Elisa Lenti,  Chisa Hidaka,  Ching-Pin Chang,  Nizar Mahlaoui,  Richard P Harvey,  Jean-Laurent Casanova,  Licia Selleri
Affiliations

Affiliation

  • 1 Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
PMID: 22560297 DOI: 10.1016/j.devcel.2012.02.009
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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