Strain-specific modifier genes governing craniofacial phenotypes.

BACKGROUND The presence of strain-specific modifier genes is known to modulate the phenotype and pathophysiology of mice harboring genetically engineered mutations. Thus, identification of genetic modifier genes is requisite to understanding control of phenotypic expression. c-Ski is a transcriptional regulator. Ski(-/-) mice on a C57BL6J (B6) background exhibit facial clefting, while Ski(-/-) mice on a 129P3 (129) background present with exencephaly. METHODS In the present study, oligonucleotide-based gene expression profiling was used to identify potential strain-specific modifier gene candidates present in wild type mice of B6 and 129 genetic backgrounds. Changes in gene expression were verified by TaqMan quantitative real-time PCR. RESULTS Steady-state levels of 89 genes demonstrated a significantly higher level of expression, and those of 68 genes demonstrated a significantly lower level of expression in the developing neural tubes from embryonic day (E) 8.5, B6 embryos when compared to expression levels in neural tubes derived from E 8.5, 129 embryos. CONCLUSIONS Based on the results from the current comparative microarray study, and taking into consideration a number of relevant published reports, several potential strain-specific gene candidates, likely to modify the craniofacial phenotypes in various knockout mouse models have been identified.

[1]  W. Alcaraz,et al.  Modifier genes and non-genetic factors reshape anatomical deficits in Zfp423-deficient mice. , 2011, Human molecular genetics.

[2]  M. Rastaldi,et al.  The Inhibiting Fc Receptor for IgG, FcγRIIB, Is a Modifier of Autoimmune Susceptibility , 2011, The Journal of Immunology.

[3]  M. Morrison,et al.  Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina , 2011, PloS one.

[4]  F. Sinner,et al.  Prolonged Depression-Like Behavior Caused by Immune Challenge: Influence of Mouse Strain and Social Environment , 2011, PloS one.

[5]  P. Stover,et al.  Shmt1 and de novo thymidylate biosynthesis underlie folate-responsive neural tube defects in mice. , 2011, The American journal of clinical nutrition.

[6]  R. Finn,et al.  Altered sensitivity to excitotoxic cell death and glutamate receptor expression between two commonly studied mouse strains , 2010, Journal of neuroscience research.

[7]  M. Yacoub,et al.  Genetic background affects function and intracellular calcium regulation of mouse hearts. , 2010, Cardiovascular research.

[8]  P. Cattini,et al.  Embryonic survival and severity of cardiac and craniofacial defects are affected by genetic background in fibroblast growth factor-16 null mice. , 2010, DNA and cell biology.

[9]  J. Affourtit,et al.  Cdcs1 a major colitis susceptibility locus in mice; Subcongenic analysis reveals genetic complexity , 2010, Inflammatory bowel diseases.

[10]  H. Oppelaar,et al.  Variations in ventral root axon morphology and locomotor behavior components across different inbred strains of mice , 2009, Neuroscience.

[11]  P. Majerus,et al.  Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5/6-kinase , 2009, Proceedings of the National Academy of Sciences.

[12]  David N. Linsenbardt,et al.  Sensitivity and tolerance to the hypnotic and ataxic effects of ethanol in adolescent and adult C57BL/6J and DBA/2J mice. , 2009, Alcoholism, clinical and experimental research.

[13]  J. Klingensmith,et al.  Chordin Is a Modifier of Tbx1 for the Craniofacial Malformations of 22q11 Deletion Syndrome Phenotypes in Mouse , 2009, PLoS genetics.

[14]  C. Kappen,et al.  Wnt signaling in caudal dysgenesis and diabetic embryopathy. , 2008, Birth defects research. Part A, Clinical and molecular teratology.

[15]  R. D'Hooge,et al.  Effect of genetic background on acoustic startle response in fragile X knockout mice. , 2008, Genetics research.

[16]  J. Mosser,et al.  Gene expression profiling of Hfe-/- liver and duodenum in mouse strains with differing susceptibilities to iron loading: identification of transcriptional regulatory targets of Hfe and potential hemochromatosis modifiers , 2007, Genome Biology.

[17]  C. Wagner,et al.  Distribution of progesterone receptor immunoreactivity in the fetal and neonatal rat forebrain , 2007, The Journal of comparative neurology.

[18]  J. Klingensmith,et al.  Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling , 2007, Development.

[19]  M. Daly,et al.  Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four , 2007, Mechanisms of Development.

[20]  J. Golden,et al.  PIP5KIγ is required for cardiovascular and neuronal development , 2007, Proceedings of the National Academy of Sciences.

[21]  R. Williams,et al.  Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors , 2007, Genes and Immunity.

[22]  A. McAllister,et al.  Estradiol Targets Synaptic Proteins to Induce Glutamatergic Synapse Formation in Cultured Hippocampal Neurons: Critical Role of Estrogen Receptor-α , 2007, The Journal of Neuroscience.

[23]  M. Ko,et al.  Expression profiling of the mouse early embryo: Reflections and perspectives , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  Ryan M. Anderson,et al.  Endogenous bone morphogenetic protein antagonists regulate mammalian neural crest generation and survival , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[25]  M. Ko,et al.  Global gene expression profiling of preimplantation embryos , 2006, Human Cell.

[26]  A. Copp.  Neurulation in the cranial region – normal and abnormal , 2005, Journal of anatomy.

[27]  P. Papachristou,et al.  Increased Wnt levels in the neural tube impair the function of adherens junctions during neurulation , 2005, Molecular and Cellular Neuroscience.

[28]  E. Martí,et al.  Morphogens in motion: growth control of the neural tube. , 2005, Journal of neurobiology.

[29]  B. Hogan,et al.  An essential role for an inositol polyphosphate multikinase, Ipk2, in mouse embryogenesis and second messenger production. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Gilbert,et al.  SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects , 2005, Human Genetics.

[31]  M. Henkemeyer,et al.  EphB receptor tyrosine kinases control morphological development of the ventral midbrain , 2005, Mechanisms of Development.

[32]  Dong-Uk Kim,et al.  Tsc-22 enhances TGF-β signaling by associating with Smad4 and induces erythroid cell differentiation , 2005, Molecular and Cellular Biochemistry.

[33]  Y. Minemoto,et al.  c-Jun N-Terminal Protein Kinase 1 (JNK1), but Not JNK2, Is Essential for Tumor Necrosis Factor Alpha-Induced c-Jun Kinase Activation and Apoptosis , 2004, Molecular and Cellular Biology.

[34]  D. Loebel,et al.  Restricted expression of ETn-related sequences during post-implantation mouse development. , 2004, Gene expression patterns : GEP.

[35]  T. Okamura,et al.  Functional analysis of mouse 3‐phosphoglycerate dehydrogenase (Phgdh) gene promoter in developing brain , 2004, Journal of neuroscience research.

[36]  Masahiko Watanabe,et al.  Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality* , 2004, Journal of Biological Chemistry.

[37]  N. Greene,et al.  Planar cell polarity genes and neural tube closure. , 2003, Birth defects research. Part C, Embryo today : reviews.

[38]  G. Schoenwolf,et al.  Differential Expression of Two Cell Adhesion Molecules, Ephrin-A5 and Integrin α6, during Cranial Neurulation in the Chick Embryo , 2003, Developmental Neuroscience.

[39]  Laure Bally-Cuif,et al.  Induction and patterning of neuronal development, and its connection to cell cycle control , 2003, Current Opinion in Neurobiology.

[40]  A. Lin.  Activation of the JNK signaling pathway: Breaking the brake on apoptosis , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[41]  D. Mager,et al.  Insertional polymorphisms of ETn retrotransposons include a disruption of the wiz gene in C57BL/6 mice , 2002, Mammalian Genome.

[42]  H. Dörr,et al.  A Cross-Sectional Study of Dehydroepiandrosterone Sulfate in Prepubertal Children with Myelomeningocele , 2002, Hormone Research in Paediatrics.

[43]  H. Blom,et al.  Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? , 2001, Molecular genetics and metabolism.

[44]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[45]  J. Frisén,et al.  Regulation of repulsion versus adhesion by different splice forms of an Eph receptor , 2000, Nature.

[46]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[47]  S. Bustin.  Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. , 2000, Journal of molecular endocrinology.

[48]  D. Mager,et al.  Novel Mouse Type D Endogenous Proviruses and ETn Elements Share Long Terminal Repeat and Internal Sequences , 2000, Journal of Virology.

[49]  M. Goumans,et al.  Expression of TGF‐β stimulated clone‐22 (TSC‐22) in mouse development and TGF‐β signalling , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[50]  E. Wagner,et al.  Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2 , 1999, Mechanisms of Development.

[51]  J. den Hertog,et al.  Transforming Growth Factor-β-stimulated Clone-22 Is a Member of a Family of Leucine Zipper Proteins That Can Homo- and Heterodimerize and Has Transcriptional Repressor Activity* , 1999, Journal of Biological Chemistry.

[52]  P. Rakic,et al.  The Jnk1 and Jnk2 Protein Kinases Are Required for Regional Specific Apoptosis during Early Brain Development , 1999, Neuron.

[53]  R. Maas,et al.  BMP7 acts in murine lens placode development. , 1999, Developmental biology.

[54]  K. Mounzih,et al.  Effect of the genetic background on the reproduction of leptin-deficient obese mice. , 1999, Endocrinology.

[55]  M. Rudnicki,et al.  Strain-dependent embryonic lethality in mice lacking the retinoblastoma-related p130 gene. , 1998, Development.

[56]  R. Khokha,et al.  Genetic background influences timing, morphology and dissemination of lymphomas in p53-deficient mice. , 1998, International journal of oncology.

[57]  H. Beug,et al.  Transformation of hematopoietic cells by the Ski oncoprotein involves repression of retinoic acid receptor signaling. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  U. Rapp,et al.  Craf-1 protein kinase is essential for mouse development , 1998, Mechanisms of Development.

[59]  C. Colmenares,et al.  Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development. , 1997, Genes & development.

[60]  K. Yanagihara,et al.  Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor beta. , 1997, The Biochemical journal.

[61]  D. Newgreen,et al.  Changes in cell adhesion and extracellular matrix molecules in spontaneous spinal neural tube defects in avian embryos. , 1997, Teratology.

[62]  M. Bronner‐Fraser,et al.  Inhibition of cranial neural crest adhesion in vitro and migration in vivo using integrin antisense oligonucleotides. , 1996, Developmental biology.

[63]  P. Chambon,et al.  Isolation of retinoic acid-repressed genes from P19 embryonal carcinoma cells. , 1996, Gene.

[64]  D. DeSimone,et al.  Integrin alpha 6 expression is required for early nervous system development in Xenopus laevis. , 1996, Development.

[65]  R. Gerlai.  Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? , 1996, Trends in Neurosciences.

[66]  L. Tsui,et al.  Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor , 1996, Nature Genetics.

[67]  M. Ferguson,et al.  Transforming growth factor–β3 is required for secondary palate fusion , 1995, Nature Genetics.

[68]  S. Aizawa,et al.  Mouse Otx2 functions in the formation and patterning of rostral head. , 1995, Genes & development.

[69]  L. Donehower,et al.  Effects of genetic background on tumorigenesis in p53‐deficient mice , 1995, Molecular carcinogenesis.

[70]  R. Krumlauf,et al.  The kreisler mouse: a hindbrain segmentation mutant that lacks two rhombomeres. , 1994, Development.

[71]  M. Karin,et al.  Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. , 1993, Genes & development.

[72]  L. Donehower,et al.  Genetic background alters the spectrum of tumors that develop in p53‐deficient mice , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[73]  T. Uede,et al.  Transcriptional repression and differential splicing of Fas mRNA by early transposon (ETn) insertion in autoimmune lpr mice. , 1993, Biochemical and biophysical research communications.

[74]  Y. Fujiwara,et al.  A novel murine zinc finger gene mapped within the tw18 deletion region expresses in germ cells and embryonic nervous system. , 1993, Developmental biology.

[75]  A. Hendrickx,et al.  Triamcinolone acetonide-induced meningocele and meningoencephalocele in rhesus monkeys. , 1990, American Journal of Pathology.

[76]  Yoshi T. Sakai.  Neurulation in the mouse: Manner and timing of neural tube closure , 1989, The Anatomical record.

[77]  M. Bronner‐Fraser.  An antibody to a receptor for fibronectin and laminin perturbs cranial neural crest development in vivo. , 1986, Developmental biology.

[78]  J. York,et al.  Roles for inositol polyphosphate kinases in the regulation of nuclear processes and developmental biology. , 2007, Advances in enzyme regulation.

[79]  J. Golden,et al.  PIP5KI gamma is required for cardiovascular and neuronal development. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[80]  M. Nakayama,et al.  Differential profiles of genes expressed in neonatal brain of 129X1/SvJ and C57BL/6J mice: A database to aid in analyzing DNA microarrays using nonisogenic gene-targeted mice. , 2003, DNA research : an international journal for rapid publication of reports on genes and genomes.

[81]  P. Schedl,et al.  Masters change, slaves remain. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[82]  Jeffrey C. Murray,et al.  Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski−/− mice , 2002, Nature Genetics.

[83]  T. Doetschman,et al.  Influence of genetic background on knockout mouse phenotypes. , 2001, Methods in molecular biology.

[84]  A. Brivanlou,et al.  Neural patterning in the vertebrate embryo. , 2001, International review of cytology.

[85]  M. Çakmak,et al.  The split notochord syndrome with dorsal enteric fistula, meningomyelocele and imperforate anus. , 1999, The Turkish journal of pediatrics.

[86]  Dr. Karl Theiler.  The House Mouse , 1989, Springer Berlin Heidelberg.