PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract.

While studies have highlighted the role of HOXA9-13 and PBX1 homeobox genes during the development of the female genital tract, the molecular mechanisms triggered by these genes are incompletely elucidated. In several developmental pathways, PBX1 binds to MEINOX family members in the cytoplasm to be imported into the nucleus where they associate with HOX proteins to form a higher complex that modulates gene expression. This concept has been challenged by a recent report showing that in some cell cultures, PBX1 nuclear localization might be regulated independently of MEINOX proteins (Kilstrup-Nielsen et al., 2003). Our work gives the first illustration of this alternative mechanism in an organogenesis process. Indeed, we show that PBX1 is mostly cytoplasmic in epithelial endometrial cells of the developing female genital tract despite the nuclear localization of MEIS1. We thus provide evidence for a control of PBX1 intracellular distribution which is independent of MEINOX proteins, but is cell cycle correlated.

[1]  N. Green,et al.  A conformational change in PBX1A is necessary for its nuclear localization. , 2000, Experimental cell research.

[2]  J. Berthelsen,et al.  The subcellular localization of PBX1 and EXD proteins depends on nuclear import and export signals and is modulated by association with PREP1 and HTH. , 1999, Genes & development.

[3]  R. Mann,et al.  Antagonism between extradenticle function and Hedgehog signalling in the developing limb , 1998, Nature.

[4]  M. Alessio,et al.  PBX1 nuclear export is regulated independently of PBX–MEINOX interaction by PKA phosphorylation of the PBC‐B domain , 2003, The EMBO journal.

[5]  C. Murre,et al.  Localization of Pbx1 transcripts in developing rat embryos , 1995, Mechanisms of Development.

[6]  David Warburton,et al.  The molecular basis of lung morphogenesis , 2000, Mechanisms of Development.

[7]  H. Taylor,et al.  A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes. , 1997, Biology of reproduction.

[8]  M. Cleary,et al.  Pbx1 is essential for adrenal development and urogenital differentiation , 2003, Genesis.

[9]  C. Allis,et al.  Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases , 2002, Molecular and Cellular Biology.

[10]  R. Warnke,et al.  Expression of Pbx1b during mammalian organogenesis , 2001, Mechanisms of Development.

[11]  D. Mortlock,et al.  Mutation of HOXA13 in hand-foot-genital syndrome , 1997, Nature Genetics.

[12]  R. Maas,et al.  Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES). , 1998, Developmental biology.

[13]  P. Scambler,et al.  Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. , 2000, American journal of human genetics.

[14]  S. Bonner-Weir,et al.  PDX:PBX complexes are required for normal proliferation of pancreatic cells during development. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Mann,et al.  Generation of multiple antagonistic domains along the proximodistal axis during Drosophila leg development. , 1998, Development.

[16]  M. Dorée,et al.  The Xenopus protein kinase pEg2 associates with the centrosome in a cell cycle-dependent manner, binds to the spindle microtubules and is involved in bipolar mitotic spindle assembly. , 1998, Journal of cell science.

[17]  M. Montminy,et al.  Pbx-Hox Heterodimers Recruit Coactivator-Corepressor Complexes in an Isoform-Specific Manner , 1999, Molecular and Cellular Biology.

[18]  J. C. Hombría,et al.  Beyond homeosis--HOX function in morphogenesis and organogenesis. , 2003, Differentiation; research in biological diversity.

[19]  H. Taylor,et al.  The Role of HOX Genes in the Development and Function of the Female Reproductive Tract , 2000, Seminars in reproductive medicine.

[20]  S. Chanda,et al.  Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. , 2001, Development.

[21]  N. Green,et al.  PBX and MEIS as Non-DNA-Binding Partners in Trimeric Complexes with HOX Proteins , 1999, Molecular and Cellular Biology.

[22]  Stéphane Deschamps,et al.  A conserved non-homeodomain Hoxa9 isoform interacting with CBP is co-expressed with the 'typical' Hoxa9 protein during embryogenesis. , 2004, Gene expression patterns : GEP.

[23]  F. Blasi,et al.  Expression of Hox cofactor genes during mouse ovarian follicular development and oocyte maturation. , 2004, Gene.

[24]  Hyung Don Ryoo,et al.  Nuclear Translocation of Extradenticle Requires homothorax , which Encodes an Extradenticle-Related Homeodomain Protein , 1997, Cell.

[25]  P. Lasko,et al.  Nonmuscle Myosin Promotes Cytoplasmic Localization of PBX , 2003, Molecular and Cellular Biology.

[26]  J. Innis,et al.  Range of HOX/TALE superclass associations and protein domain requirements for HOXA13:MEIS interaction. , 2005, Developmental biology.

[27]  L. Kömüves,et al.  HOXA9 Forms Triple Complexes with PBX2 and MEIS1 in Myeloid Cells , 1999, Molecular and Cellular Biology.

[28]  R. Mann,et al.  Control of the nuclear localization of Extradenticle by competing nuclear import and export signals. , 1999, Genes & development.

[29]  C. Tickle,et al.  HOX-4 genes and the morphogenesis of mammalian genitalia. , 1991, Genes & development.

[30]  D. Duboule,et al.  Antagonists Go out on a Limb , 1999, Cell.

[31]  P. Brown,et al.  Gene expression patterns in human placenta. , 2006, Proceedings of the National Academy of Sciences of the United States of America.