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

Abstract

SUMMARY 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 down-regulation 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.

Pbx1 is required for adult SVZ neurogenesis

“…Because PBX2 colocalizes with PBX1 in the SVZ ( Fig. 1) and is known to compensate for loss of Pbx1 in embryonic domains of co-expression, we crossed the conditional Pbx1 mutant strain to a mouse line homozygous mutant for Pbx2 to obtain Pbx1 fl/fl ;Pbx2 −/− compound mutant animals (Capellini et al, 2011;Ferretti et al, 2011;Koss et al, 2012;Selleri et al, 2004). Mice with a constitutive knockout of Pbx2 are viable and show no obvious phenotype .…”

“…To investigate whether Pbx1 has a role in neural cell fate specification, we used a conditional allele of Pbx1 (Pbx1 fl/fl ) that allows Cre-mediated deletion of exon 3 of the Pbx1 gene (Koss et al, 2012). PBX1 immunoreactivity was lost within 48 h when aNSs derived from Pbx1 fl/fl mice were infected with retroviruses carrying Cre recombinase together with an IRES-GFP cassette (Cre-GFP; Fig.…”

“…Genes encoding PBC class HD proteins share a high degree of sequence homology and have overlapping functions in domains of co-expression in vivo (Capellini et al, 2011). In fact, select developmental defects associated with Pbx1 loss-of-function were only uncovered when the Pbx1 deficiency was combined with homozygous or heterozygous loss of Pbx2 or Pbx3 (Capellini et al, 2011;Ferretti et al, 2011;Koss et al, 2012). Mechanistically, PBX1 associates with members of the MEIS/PREP subclass of TALE-HD proteins, but can also form heteromeric complexes with HOX proteins, non-HOX HD-containing proteins, bHLH or PAX proteins (Ladam and Sagerström, 2014;Longobardi et al, 2014;).…”

“…They contribute to the correct patterning of the anterior-posterior body axis, confer regional identity and are involved in the regulation of proliferation, apoptosis and differentiation (Berkes et al, 2004;Ferretti et al, 2011;Gordon et al, 2011;Koss et al, 2012;Yao et al, 2013). Pbx1 participates in many developmental processes, as demonstrated by the complex phenotypes associated with Pbx1 loss-of-function in mice (Brendolan et al, 2005;DiMartino et al, 2001;Ferretti et al, 2011;Golonzhka et al, 2015;Koss et al, 2012;Manley et al, 2004;Stankunas et al, 2008;Vitobello et al, 2011). Genes encoding PBC class HD proteins share a high degree of sequence homology and have overlapping functions in domains of co-expression in vivo (Capellini et al, 2011).…”

Pbx1 activates Fgf10 in the mesenchyme of developing lungs

“…f/f (Koss et al, 2012) and Islet1Cre (Cai et al, 2003;Yang et al, 2006) mice have been described previously. The date of observing a vaginal plug was set as E0.5, and embryonic development was confirmed by ultrasonography before sacrificing pregnant mice (Chang et al, 2003).…”