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

被引：60

作者：

Koss, Matthew ^{[1
]}

Bolze, Alexandre ^{[2
,3
]}

Brendolan, Andrea ^{[1
,4
]}

Saggese, Matilde ^{[1
]}

Capellini, Terence D. ^{[1
]}

Bojilova, Ekaterina ^{[1
]}

Boisson, Bertrand ^{[2
]}

Prall, Owen W. J. ^{[5
]}

Elliott, David A. ^{[5
]}

Solloway, Mark ^{[5
]}

Lenti, Elisa ^{[4
]}

Hidaka, Chisa ^{[6
]}

Chang, Ching-Pin ^{[7
]}

Mahlaoui, Nizar ^{[8
]}

Harvey, Richard P. ^{[5
,9
]}

Casanova, Jean-Laurent ^{[2
,3
,8
,10
]}

Selleri, Licia ^{[1
]}

机构：

[1] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA

[2] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA

[3] Univ Paris 05, F-75015 Paris, France

[4] Ist Sci San Raffaele, Lab Lymphoid Organ Dev, I-20132 Milan, Italy

[5] Victor Chang Cardiac Res Inst, Darlinghurst, NSW 2010, Australia

[6] Hosp Special Surg, Lab Soft Tissue Res, New York, NY 10021 USA

[7] Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[8] Hop Necker Enfants Malad, AP HP, Pediat Hematol Immunol Unit, F-75015 Paris, France

[9] Univ New S Wales, Fac Med, St Vincents Clin Sch, Kensington, NSW 2052, Australia

[10] INSERM, U980, Necker Med Sch, Lab Human Genet Infect Dis,Necker Branch, F-75015 Paris, France

来源：

DEVELOPMENTAL CELL | 2012年 / 22卷 / 05期

基金：

英国医学研究理事会;

关键词：

SEQUENCING-BASED DISCOVERY; FACTOR NKX2-5; SPLEEN; P15(INK4B); CELLS; IDENTIFICATION; PROLIFERATION; REQUIREMENT; EXPRESSION; DISRUPTS;

D O I：

10.1016/j.devcel.2012.02.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：913 / 926

页数：14

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