title: Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module.
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.
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Koss
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bolze
authors.forename: Andrea
authors.initials: A
authors.lastname: Brendolan
authors.forename: Matilde
authors.initials: M
authors.lastname: Saggese
authors.forename: Terence D
authors.initials: TD
authors.lastname: Capellini
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bojilova
authors.forename: Bertrand
authors.initials: B
authors.lastname: Boisson
authors.forename: Owen W J
authors.initials: OW
authors.lastname: Prall
authors.forename: David A
authors.initials: DA
authors.lastname: Elliott
authors.forename: Mark
authors.initials: M
authors.lastname: Solloway
authors.forename: Elisa
authors.initials: E
authors.lastname: Lenti
authors.forename: Chisa
authors.initials: C
authors.lastname: Hidaka
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000172:deficiency; D013154:Spleen / Q000002:abnormalities*; D013158:Splenic Diseases / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C493966:CDKN2B protein, human; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human