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

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• 作者：Matthew Koss¹ ; Alexandre Bolze² ; ³ ; ¹¹ ; Andrea Brendolan¹ ; ⁴ ; ¹¹ ; Matilde Saggese¹ ; Terence  ; D. Capellini¹ ; ¹² ; Ekaterina Bojilova¹ ; Bertrand Boisson² ; Owen  ; W.J. Prall⁵ ; ¹³ ; David A. Elliott⁵ ; ¹⁴ ; Mark Solloway⁵ ; ¹⁵ ; Elisa Lenti⁴ ; Chisa Hidaka⁶ ; Ching-Pin Chang⁷ ; Nizar Mahlaoui⁸ ; Richard  ; P. Harvey⁵ ; ⁹ ; Jean-Laurent Casanova² ; ³ ; ⁸ ; ¹⁰ ; Licia Selleri¹ ; ^{lis2008@med.cornell.edu}
• 刊名：Developmental Cell
• 出版年：2012
• 期刊代码：10_15345807
• 类别：bio
• 出版时间：15 May, 2012
• 卷：22
• 期：5
• 页码：913-926
• 文件大小：2708 K

摘要

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class="h3">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 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聽vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.