Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

Matthew Koss; Alexandra Bolze; Andrea Brendolan; Matilde Saggese; Terence D Capellini; Ekaterina Bojilova; Bertrand Bolsson; Owen WJ Prall; David A Elliott; Mark J Solloway; Elisa Lenti; Chisa Hidaka; Ching-Pin Chang; Nizar Mazhlaoui; Richard P Harvey; Jean-Laurent Casanova; Licia Selleri

doi:10.1016/j.devcel.2012.02.009

Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

Matthew Koss, Alexandra Bolze, Andrea Brendolan, Matilde Saggese, Terence D Capellini, Ekaterina Bojilova, Bertrand Bolsson, Owen WJ Prall, David A Elliott, Mark J Solloway, Elisa Lenti, Chisa Hidaka, Ching-Pin Chang, Nizar Mazhlaoui, Richard P Harvey, Jean-Laurent Casanova, Licia Selleri

Research output: Contribution to journal › Article › Research › peer-review

52 Citations (Scopus)

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.

Original language	English
Pages (from-to)	913 - 926
Number of pages	14
Journal	Developmental Cell
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2012.02.009
Publication status	Published - 2012

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Koss, M., Bolze, A., Brendolan, A., Saggese, M., Capellini, T. D., Bojilova, E., Bolsson, B., Prall, O. WJ., Elliott, D. A., Solloway, M. J., Lenti, E., Hidaka, C., Chang, C-P., Mazhlaoui, N., Harvey, R. P., Casanova, J-L., & Selleri, L. (2012). Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Developmental Cell, 22(5), 913 - 926. https://doi.org/10.1016/j.devcel.2012.02.009

Koss, Matthew ; Bolze, Alexandra ; Brendolan, Andrea ; Saggese, Matilde ; Capellini, Terence D ; Bojilova, Ekaterina ; Bolsson, Bertrand ; Prall, Owen WJ ; Elliott, David A ; Solloway, Mark J ; Lenti, Elisa ; Hidaka, Chisa ; Chang, Ching-Pin ; Mazhlaoui, Nizar ; Harvey, Richard P ; Casanova, Jean-Laurent ; Selleri, Licia. / Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. In: Developmental Cell. 2012 ; Vol. 22, No. 5. pp. 913 - 926.

@article{6d91760c574442b8a36ddd552a4c1d8e,

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.",

author = "Matthew Koss and Alexandra Bolze and Andrea Brendolan and Matilde Saggese and Capellini, {Terence D} and Ekaterina Bojilova and Bertrand Bolsson and Prall, {Owen WJ} and Elliott, {David A} and Solloway, {Mark J} and Elisa Lenti and Chisa Hidaka and Ching-Pin Chang and Nizar Mazhlaoui and Harvey, {Richard P} and Jean-Laurent Casanova and Licia Selleri",

year = "2012",

doi = "10.1016/j.devcel.2012.02.009",

language = "English",

volume = "22",

pages = "913 -- 926",

journal = "Developmental Cell",

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number = "5",

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Koss, M, Bolze, A, Brendolan, A, Saggese, M, Capellini, TD, Bojilova, E, Bolsson, B, Prall, OWJ, Elliott, DA, Solloway, MJ, Lenti, E, Hidaka, C, Chang, C-P, Mazhlaoui, N, Harvey, RP, Casanova, J-L & Selleri, L 2012, 'Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module', Developmental Cell, vol. 22, no. 5, pp. 913 - 926. https://doi.org/10.1016/j.devcel.2012.02.009

Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. / Koss, Matthew; Bolze, Alexandra; Brendolan, Andrea; Saggese, Matilde; Capellini, Terence D; Bojilova, Ekaterina; Bolsson, Bertrand; Prall, Owen WJ; Elliott, David A; Solloway, Mark J; Lenti, Elisa; Hidaka, Chisa; Chang, Ching-Pin; Mazhlaoui, Nizar; Harvey, Richard P; Casanova, Jean-Laurent; Selleri, Licia.

In: Developmental Cell, Vol. 22, No. 5, 2012, p. 913 - 926.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module

AU - Koss, Matthew

AU - Bolze, Alexandra

AU - Brendolan, Andrea

AU - Saggese, Matilde

AU - Capellini, Terence D

AU - Bojilova, Ekaterina

AU - Bolsson, Bertrand

AU - Prall, Owen WJ

AU - Elliott, David A

AU - Solloway, Mark J

AU - Lenti, Elisa

AU - Hidaka, Chisa

AU - Chang, Ching-Pin

AU - Mazhlaoui, Nizar

AU - Harvey, Richard P

AU - Casanova, Jean-Laurent

AU - Selleri, Licia

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

UR - http://www.sciencedirect.com/science/article/pii/S1534580712000901

U2 - 10.1016/j.devcel.2012.02.009

DO - 10.1016/j.devcel.2012.02.009

M3 - Article

VL - 22

SP - 913

EP - 926

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 5

ER -