Koss, Matthew and Bolze, Alexandre and Brendolan, Andrea and Saggese, Matilde and Capellini, Terence D and Bojilova, Ekaterina and Boisson, Bertrand and Prall, Owen W J and Elliott, David A and Solloway, Mark and Lenti, Elisa and Hidaka, Chisa and Chang, Ching-Pin and Mahlaoui, Nizar and Harvey, Richard P and Casanova, Jean-Laurent and Selleri, Licia (2012) Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Developmental cell, 22 (5). pp.913-26. ISSN 1878-1551 (PMC OA)
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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. (NIH grant no HD43997, HD061403, and DE18031 and HL085345, The March of Dimes and Birth Defects Foundation (6-FY03-071), etc)
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Divisions: | Faculty of Law, Arts and Social Sciences > School of Education |
| Depositing User: | Repository Administrator |
| Date Deposited: | 11 Dec 2015 02:03 |
| Last Modified: | 21 Jan 2016 23:35 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/9 |
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