1: Brain Res Brain Res Rev. 2005 Sep;49(2):120-6. Epub 2005 Jan 21. Isthmus organizer for midbrain and hindbrain development. Nakamura H, Katahira T, Matsunaga E, Sato T. Department of Molecular Neurobiology, Graduate School of Life Sciences and Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan. nakamura@idac.tohoku.ac.jp Classical transplantation studies showed that the isthmus has an organizing activity upon the tectum and cerebellum. Since Fgf8 is expressed in the isthmus and mimics functionally isthmic grafts, it is accepted that Fgf8 plays pivotal role in the isthmic organizing activity. The fate of brain vesicles is determined by the combinations of transcription factors. The neural tube region where Otx2, Pax2, and En1 are expressed early on acquires midbrain identity. Pax3/7 forces the midbrain to differentiate into tectum. En1/2, Pax2/5, and Fgf8 form a positive feedback loop for their expression, thus misexpression of one of these molecules turns on the loop and forces presumptive diencephalon to differentiate into tectum. The isthmic organizer signal, Fgf8, stabilizes or changes the expression of the transcription factors in mid/hindbrain region. A strong Fgf8 signal activates the Ras-ERK signaling pathway, which in turn activates Irx2 in a rostrodorsal part of the hindbrain, and forces this tissue to differentiate into cerebellum. Publication Types: Review PMID: 16111543 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 2: Int J Dev Biol. 2005;49(2-3):231-5. Isthmus organizer and regionalization of the mesencephalon and metencephalon. Nakamura H, Watanabe Y. Department of Molecular Neurobiology, Graduate School of Life Sciences and Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. nakamura@idac.tohoku.ac.jp The brain vesicles that are formed at an early stage of neural development are the fundamentals of the brain plan. Heterotopic transplantation revealed that the diencephalon could change its fate when juxtaposed to the isthmus (mes-metencephalic boundary), which indicated that the isthmus functions as an organizer for the mesencephalon and metencephalon. Fgf8 is identified as an isthmus organizing signal. Misexpression of Fgf8a and Fgf8b indicated that a strong Fgf8 signal organizes cerebellar development. The transcription factors define the fate of the region. Overlapping expression of Otx2, En1 and Pax2 may define the mesencephalic region and additional expression of Pax3/7 may instruct the mesencephalic region to differentiate into the tectum. The di-mesencephalic boundary is determined by repressive interaction between Pax6 and En1/Pax2 and the mes-metencephalic boundary is defined by repressive interaction between Otx2 and Gbx2. Fgf8 is induced at the border of the Otx2 and Gbx2 expression domain, overlapping with Gbx2 expression. Publication Types: Review Review, Tutorial PMID: 15906236 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 3: Dev Biol. 2004 Jul 15;271(2):439-66. Molecular anatomy of placode development in Xenopus laevis. Schlosser G, Ahrens K. Brain Research Institute, University of Bremen, 28334 Bremen, Germany. gschloss@uni-bremen.de We analyzed the spatiotemporal pattern of expression of 15 transcription factors (Six1, Six4, Eya1, Sox3, Sox2, Pax6, Pax3, Pax2, Pax8, Dlx3, Msx1, FoxI1c, Tbx2, Tbx3, Xiro1) during placode development in Xenopus laevis from neural plate to late tail bud stages. Out of all genes investigated, only the expression of Eya1, Six1, and Six4 is maintained in all types of placode (except the lens) throughout embryonic development, suggesting that they may promote generic placodal properties and that their crescent-shaped expression domain surrounding the neural plate defines a panplacodal primordium from which all types of placode originate. Double-labeling procedures were employed to reveal the precise position of this panplacodal primordium relative to neural plate, neural crest, and other placodal markers. Already at neural plate stages, the panplacodal primordium is subdivided into several subregions defined by particular combinations of transcription factors allowing us to identify the approximate regions of origin of various types of placode. Whereas some types of placode were already prefigured by molecularly distinct areas at neural plate stages, the epibranchial, otic, and lateral line placodes arise from a common posterior placodal area (characterized by Pax8 and Pax2 expression) and acquire differential molecular signatures only after neural tube closure. Our findings argue for a multistep mechanism of placode induction, support a combinatorial model of placode specification, and suggest that different placodes evolved from a common placodal primordium by successive recruitment of new inducers and target genes. PMID: 15223346 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 4: Klin Oczna. 2003;105(3-4):207-10. [Formation of congenital defects during ocular development. II. Genetic background of oculogenesis and developmental birth defects] [Article in Polish] Krawczynski MR. Pracowni Poradnictwa Genetycznego w Chorobach Narzadu Wzroku Katedry, Zakladu Genetyki Medycznej Akademii Medycznej w Poznaniu. The course of oculogenesis is genetically controlled by genes, that are selectively expressed in the developing eye. Many of them, first recognized in studies on model animals, such as fruit fly (Drosophila melanogaster) proved, that they play similar roles in humans. The crucial role in cascade of genetic control of oculogenesis plays a system of genes PAX6-EYA1/SIX3-DACH1. In this work there are described also other genes, that form a network of interactions and regulations, such as: BMP4, BMP7, OPTX2, SOX1, PAX2, PITX2, PAX3, CHX10 and other genes. Describing function of each gene, author presented simultaneously all known congenital defects and syndromes, that are caused by mutations of above mentioned genes, such as: aniridia, anophthalmia, Peters anomaly and others. Publication Types: Review Review, Tutorial PMID: 14552188 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 5: Oncogene. 2003 Sep 11;22(39):7989-97. Paired-Box genes are frequently expressed in cancer and often required for cancer cell survival. Muratovska A, Zhou C, He S, Goodyer P, Eccles MR. Department of Pathology, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand. The paired-box (PAX) genes encode a family of nine well-characterized paired-box transcription factors, with important roles in development and disease. Although PAX genes are primarily expressed in the embryo, constitutive expression promotes tissue hyperplasia. Rare tumor-specific mutations of PAX genes implicate an oncogenic role, and persistent PAX expression characterizes several tumors. Yet, a cancer-wide analysis of PAX gene expression to investigate a general role for PAX genes has not been performed. We analysed the pattern and requirement for PAX gene expression in a panel of common cancer cell lines. Very frequent PAX gene expression was identified in tumor cell lines, including lymphoma, breast, ovarian, lung, and colon cancer. In addition, the PAX2 gene was frequently expressed in a panel of 406 common primary tumor tissues. Apoptosis was rapidly induced in ovarian and bladder cancer cell lines following RNA interference to silence PAX2 expression, despite concomitant TP53 and/or HRAS mutations. These data suggest that PAX genes are frequently expressed in cancer, and that endogenous PAX gene expression is required for the growth and survival of cancer cells. PMID: 12970747 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 6: Development. 2001 Oct;128(20):4069-77. Role of Pax3/7 in the tectum regionalization. Matsunaga E, Araki I, Nakamura H. Department of Molecular Neurobiology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan. Pax3/7 is expressed in the alar plate of the mesencephalon. The optic tectum differentiates from the alar plate of the mesencephalon, and expression of Pax3/7 is well correlated to the tectum development. To explore the function of Pax3 and Pax7 in the tectum development, we misexpressed Pax3 and Pax7 in the diencephalon and ventral mesencephalon. Morphological and molecular marker gene analysis indicated that Pax3 and Pax7 misexpression caused fate change of the alar plate of the presumptive diencephalon to that of the mesencephalon, that is, a tectum and a torus semicircularis were formed ectopically. Ectopic tectum in the diencephalon appeared to be generated through sequential induction of Fgf8, En2 and Pax3/7. In ventral mesencephalon, which expresses En but does not differentiate to the tectum in normal development, Pax3 and Pax7 misexpression induced ectopic tectum. In normal development, Pax3 and Pax7 expression in the mesencephalon commences after Otx2, En and Pax2/5 expression. In addition, expression domain of Pax3 and Pax7 is well consistent with presumptive tectum region in a dorsoventral axis. Taken together with normal expression pattern of Pax3 and Pax7, results of misexpression experiments suggest that Pax3 and Pax7 define the tectum region subsequent to the function of Otx2 and En. PMID: 11641229 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 7: Oncogene. 2000 Jun 8;19(25):2921-9. Transcriptional modulation of the anti-apoptotic protein BCL-XL by the paired box transcription factors PAX3 and PAX3/FKHR. Margue CM, Bernasconi M, Barr FG, Schafer BW. Institute of Biochemistry, ETH Zurich, Switzerland. The aberrant expression of the transcription factors PAX3 and PAX3/FKHR associated with rhabdomyosarcoma (RMS), solid tumors displaying muscle cell features, suggests that these proteins play an important role in the pathogenesis of RMS. We could previously demonstrate that one of the oncogenic functions of PAX3 and PAX3/FKHR in RMS is protection from apoptosis. BCL-XL is a prominent anti-apoptotic protein present in normal skeletal muscle and RMS cells. In the present study, we establish that BCL-XL is transcriptionally modulated by PAX3 and PAX3/FKHR, since enhanced expression of both PAX proteins stimulates transcription of endogenous BCL-XL mRNA in a cell type specific manner. Further, we present evidence that both PAX3 and PAX3/FKHR can transcriptionally activate the Bcl-x gene promoter in cotransfection assays. Using electrophoretic mobility shift assays, an ATTA binding site for PAX3 and PAX3/FKHR could be localized in the upstream promoter region (position -42 to -39). Finally, ectopic overexpression of either PAX3, PAX3/FKHR or BCL-XL can rescue tumor cells from apoptosis induced by antisense treatment. These results suggest that at least part of the anti-apoptotic effect of PAX3 and PAX3/FKHR is mediated through direct transcriptional modulation of the prominent anti-apoptotic protein BCL-XL. Oncogene (2000). PMID: 10871843 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 8: Development. 2000 Jul;127(14):3045-56. Establishing neuronal identity in vertebrate neurogenic placodes. Baker CV, Bronner-Fraser M. Division of Biology, Beckman Institute 139-74, California Institute of Technology, Pasadena, California 91125, USA. cbaker@caltech.edu The trigeminal and epibranchial placodes of vertebrate embryos form different types of sensory neurons. The trigeminal placodes form cutaneous sensory neurons that innervate the face and jaws, while the epibranchial placodes (geniculate, petrosal and nodose) form visceral sensory neurons that innervate taste buds and visceral organs. In the chick embryo, the ophthalmic trigeminal (opV) placode expresses the paired homeodomain transcription factor Pax3 from very early stages, while the epibranchial placodes express Pax2. Here, we show that Pax3 expression in explanted opV placode ectoderm correlates at the single cell level with neuronal specification and with commitment to an opV fate. When opV (trigeminal) ectoderm is grafted in place of the nodose (epibranchial) placode, Pax3-expressing cells form Pax3-positive neurons on the same schedule as in the opV placode. In contrast, Pax3-negative cells in the grafted ectoderm are induced to express the epibranchial placode marker Pax2 and form neurons in the nodose ganglion that express the epibranchial neuron marker Phox2a on the same schedule as host nodose neurons. They also project neurites along central and peripheral nodose neurite pathways and survive until well after the main period of cell death in the nodose ganglion. The older the opV ectoderm is at the time of grafting, the more Pax3-positive cells it contains and the more committed it is to an opV fate. Our results suggest that, within the neurogenic placodes, there does not appear to be a two-step induction of 'generic' neurons followed by specification of the neuron to a particular fate. Instead, there seems to be a one-step induction in which neuronal subtype identity is coupled to neuronal differentiation. PMID: 10862742 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 9: Mol Cell Biol. 1999 Mar;19(3):2231-41. The highly conserved beta-hairpin of the paired DNA-binding domain is required for assembly of Pax-Ets ternary complexes. Wheat W, Fitzsimmons D, Lennox H, Krautkramer SR, Gentile LN, McIntosh LP, Hagman J. Division of Basic Immunology, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. Pax family transcription factors bind DNA through the paired domain. This domain, which is comprised of two helix-turn-helix motifs and a beta-hairpin structure, is a target of mutations in congenital disorders of mice and humans. Previously, we showed that Pax-5 (B-cell-specific activator protein) recruits proteins of the Ets proto-oncogene family to bind a composite DNA site that is essential for efficient transcription of the early-B-cell-specific mb-1 promoter. Here, evidence is provided for specific interactions between Ets-1 and the amino-terminal subdomains of Pax proteins. By tethering deletion fragments of Pax-5 to a heterologous DNA-binding domain, we show that 73 amino acids (amino acids 12 to 84) of its amino-terminal subdomain can recruit the ETS domain of Ets-1 to bind the composite site. Furthermore, an amino acid (Gln22) within the highly conserved beta-hairpin motif of Pax-5 is essential for efficient recruitment of Ets-1. The ability to recruit Ets proteins to bind DNA is a shared property of Pax proteins, as demonstrated by cooperative DNA binding of Ets-1 with sequences derived from the paired domains of Pax-2 and Pax-3. The strict conservation of sequences required for recruitment of Ets proteins suggests that Pax-Ets interactions are important for regulating transcription in diverse tissues during cellular differentiation. PMID: 10022910 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 10: Bioessays. 1997 Sep;19(9):755-65. Pax genes and organogenesis. Dahl E, Koseki H, Balling R. GSF-National Research Center for Environment and Health, Institute for Mammalian Genetics, Neuherberg, Germany. Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing genes were detected in Drosophila melanogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out of nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (PAX3), Aniridia (PAX6), Peter's anomaly (PAX6), renal coloboma syndrome (PAX2) or spontaneous mouse mutants (undulated (Pax1), Splotch (Pax3), Small eye (Pax6), Pax2(1)Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax genes are involved in pattern formation during embryogenesis, possibly by determining the time and place of organ initiation or morphogenesis. For most tissues, however, the nature of the primary developmental action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position-specific regulation of cell proliferation. Publication Types: Review Review, Tutorial PMID: 9297966 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 11: Curr Opin Cell Biol. 1996 Dec;8(6):851-7. Pax genes and their roles in cell differentiation and development. Mansouri A, Hallonet M, Gruss P. Department of Molecular Cell Biology, Max-Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Gottingen, Germany. amansou@gwdg.de Members of the Pax gene family are expressed in various tissues during ontogenesis. Evidence for their crucial role in morphogenesis, organogenesis, cell differentiation and oncogenesis is provided by rodent mutants and human diseases. Additionally, recent experimental in vivo and in vitro approaches have led to the identification of molecules that interact with Pax proteins. Publication Types: Review Review, Tutorial PMID: 8939674 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 12: Curr Opin Genet Dev. 1996 Jun;6(3):334-42. Transcription factors in disease. Engelkamp D, van Heyningen V. MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK. dieter@hgu.mrc.ac.uk Mutations affecting several predominantly tissue-specific transcriptional regulators have recently been associated with disease phenotypes. Although the mutational spectrum is variable, many of the reported cases involve clear loss-of-function mutations-such as Waardenburg syndrome type 1, aniridia and Rubinstein-Taybi syndrome-suggesting that the genetic mechanism involved in disease is haplo-insufficiency. The high degree of dosage sensitivity often appears to affect only a subset of the tissues that express the gene. Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13. Publication Types: Review Review, Tutorial PMID: 8791518 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 13: Gene. 1995 Sep 11;162(2):267-70. Identification of DNA recognition sequences for the Pax3 paired domain. Chalepakis G, Gruss P. Max-Planck Institute for Biophysical Chemistry, Gottingen, Germany. The Pax gene family, encoding transcription factors, has been classified into four subfamilies according to their genomic organization, the sequences of the paired domains (PD) and the expression pattern. Pax1 and Pax9 constitute one subfamily, Pax2, Pax5 and Pax8 another, Pax3 and Pax7 another one and Pax4 and Pax6 the fourth subfamily. The PD exhibits DNA-binding activity, and is the most conserved functional motif in all Pax proteins. A high-resolution analysis of a PD structure has been performed [Xu et al., Cell 80 (1995) 639-650] and the DNA-binding characteristics of members of two Pax subfamilies (Pax2, Pax5 and Pax6) have been determined. Here, we have utilized a PCR-based selection approach to identify the DNA-binding sequences of the Pax3/PD, a member of a subfamily which has not yet been characterized. Comparison of the Pax3/PD-binding sequences with those of other PD proteins revealed both similarities and differences in the DNA-recognition sequence. This suggests that different Pax proteins can regulate the expression of the same target gene, but they can also regulate the expression of completely unrelated genes by binding to their DNA regulatory regions. PMID: 7557441 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 14: J Cell Biol. 1994 Apr;125(2):417-25. Differential induction of Pax genes by NGF and BDNF in cerebellar primary cultures. Kioussi C, Gruss P. Abteilung fur Molekular Zellbiologie, Max-Planck Institut fur Biophysikalische Chemie, Gottingen, Germany. The Pax genes encode sequence-specific DNA binding transcription factors that are expressed in embryonic development of the nervous system. Primary neuronal cell cultures derived from the cerebellar cortex of embryonic day 14, newborn and 7-d old mice, were used to investigate the cell-type specific expression patterns of three members of the murine paired box containing gene family (Pax gene family), in vitro. Cell types which express Pax-2, Pax-3, and Pax-6 RNA in primary cultures correspond to those found in regions of the cerebellum which show RNA signals in sections of the developing mouse brain. To find mechanisms regulating Pax gene expression during cerebellar development, the differential regulation of Pax-2, Pax-3, and Pax-6 by NGF and BDNF, two structurally related neurotrophins, was studied in such primary cultures. Pax-2 and Pax-6 RNA increased slightly by 1 h and remained elevated throughout a 24-h treatment with BDNF and NGF. Pax-3 RNA was not detected in newborn cultures, but underwent a rapid (1 h) and transient (2 h) induction upon treatment with either BDNF or NGF. No response was seen with EGF or FGF. Cycloheximide treatment amplified Pax-3 induction and prolonged the signal. Thus, Pax-3 induction resembles that of the immediate-early gene c-fos, which transduces growth factor signals during the development of particular neuronal/glial cell types. The changes in Pax expression were inductive rather than trophic. PMID: 8163557 [PubMed - indexed for MEDLINE] --------------------------------------------------------------- 15: Cell. 1992 May 29;69(5):719-22. Pax in development. Gruss P, Walther C. Max Planck Institute for Biophysical Chemistry, Department of Molecular Cell Biology, Gottingen, Germany. Publication Types: Review Review, Tutorial PMID: 1591773 [PubMed - indexed for MEDLINE] ---------------------------------------------------------------