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: 9.71). 05/2012; 22(5):913-26. DOI: 10.1016/j.devcel.2012.02.009
Source: PubMed


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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    No preview · Article · May 2014 · Human Mutation
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    • "These findings reveal a previously unknown mechanism for generating distinct subsets of spleen stromal cells. RESULTS Coexpression of Nkx2-5 and Islet1 Is Confined to the Newly Specified Spleen Mesenchymal Progenitors Given that both Nkx2-5 and Islet1 are expressed at E10–10.5 in the dorsal pancreatic mesenchyme (Ahlgren et al., 1997; Hecksher-Sørensen et al., 2004) and that Nkx2-5 marks the newly specified progenitors of the SPM (Brendolan et al., 2005; Burn et al., 2008; Koss et al., 2012), we sought to test whether Islet1 is also expressed in spleen mesenchymal progenitors. Immunofluorescence analyses performed on transverse E10.5 mouse sections revealed colocalization of Nkx2-5 and Islet1 proteins in mesenchymal cells of the SPM (Figure 1A). "
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