A 5.5-kb enhancer is both necessary and sufficient for regulation of Wnt-1 transcription in vivo.

Wnt-1 encodes a secreted signaling molecule which is required for development of the midbrain and anterior hindbrain in the mouse. Wnt-1 expression is initiated early in the development of the central nervous system in a region predicted to give rise to the midbrain. Later in development Wnt-1 expression is restricted to regions of the forebrain, midbrain, and spinal cord. Previous studies identified a 5.5-kb enhancer in the Wnt-1 locus which is sufficient to activate transcription of a reporter gene in a pattern very similar to that of the endogenous Wnt-1 gene. Here we have assessed if this enhancer is an important component of the endogenous regulatory sequences of Wnt-1 by gene targeting and by testing if it is able to express Wnt-1 in a pattern which is sufficient to rescue the phenotype of loss of Wnt-1. Our results show that the 5.5-kb enhancer is both necessary and sufficient for Wnt-1 expression in vivo.

[1]  A. McMahon,et al.  Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. , 1997, Development.

[2]  J. Collignon,et al.  nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. , 1997, Development.

[3]  Andrew Lumsden,et al.  Patterning the Vertebrate Neuraxis , 1996, Science.

[4]  R. Beddington,et al.  Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo , 1996, Current Biology.

[5]  Andrew P. McMahon,et al.  Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development , 1996, Nature.

[6]  J. Rubenstein,et al.  Longitudinal organization of the anterior neural plate and neural tube. , 1995, Development.

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

[8]  P. Brûlet,et al.  Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. , 1995, Development.

[9]  T. Ley,et al.  Targeted deletion of 5'HS2 of the murine beta-globin LCR reveals that it is not essential for proper regulation of the beta-globin locus. , 1995, Genes & development.

[10]  A. McMahon,et al.  Development of midbrain and anterior hindbrain ocular motoneurons in normal and Wnt-1 knockout mice. , 1995, Journal of neurobiology.

[11]  Andrew P. McMahon,et al.  Pax-2 expression in the murine neural plate precedes and encompasses the expression domains of Wnt-1 and En-1 , 1995, Mechanisms of Development.

[12]  P. Good,et al.  Dorsal-ventral patterning and differentiation of noggin-induced neural tissue in the absence of mesoderm. , 1995, Development.

[13]  R. Behringer,et al.  Requirement for LIml in head-organizer function , 1995, Nature.

[14]  J. Miyazaki,et al.  Site-specific recombination of a transgene in fertilized eggs by transient expression of Cre recombinase. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Rossant,et al.  Positive and negative signals from mesoderm regulate the expression of mouse Otx2 in ectoderm explants. , 1994, Development.

[16]  A. McMahon,et al.  Cis-acting regulatory sequences governing Wnt-1 expression in the developing mouse CNS. , 1994, Development.

[17]  R. Krumlauf.  Hox genes in vertebrate development , 1994, Cell.

[18]  R. Krumlauf,et al.  Evidence for a mitogenic effect of Wnt-1 in the developing mammalian central nervous system. , 1994, Development.

[19]  A. McMahon,et al.  Wnt-3a regulates somite and tailbud formation in the mouse embryo. , 1994, Genes & development.

[20]  P. Swiatek,et al.  Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. , 1993, Genes & development.

[21]  A. McMahon,et al.  Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds. , 1993, Development.

[22]  K. Rajewsky,et al.  Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting , 1993, Cell.

[23]  J. Rossant,et al.  Anterior mesendoderm induces mouse Engrailed genes in explant cultures. , 1993, Development.

[24]  J. M. W. Slack,et al.  The zootype and the phylotypic stage , 1993, Nature.

[25]  A. Joyner,et al.  The midbrain-hindbrain phenotype of Wnt-1− Wnt-1− mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum , 1992, Cell.

[26]  M. Capecchi,et al.  Swaying is a mutant allele of the proto-oncogene Wnt-1 , 1991, Cell.

[27]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[28]  A. Joyner,et al.  Examining pattern formation in mouse, chicken and frog embryos with an En-specific antiserum. , 1991, Development.

[29]  Andrew P. McMahon,et al.  The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain , 1990, Cell.

[30]  Mario R. Capecchi,et al.  Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development , 1990, Nature.

[31]  R. Nusse,et al.  The Wnt-1 (int-1) oncogene promoter and its mechanism of activation by insertion of proviral DNA of the mouse mammary tumor virus , 1990, Molecular and cellular biology.

[32]  A. Joyner,et al.  Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development. , 1988, Genes & development.

[33]  Mario R. Capecchi,et al.  Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes , 1988, Nature.

[34]  H. Varmus,et al.  Expression of the proto-oncogene int-1 is restricted to postmeiotic male germ cells and the neural tube of mid-gestational embryos , 1987, Cell.

[35]  A. McMahon,et al.  Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo , 1987, Cell.

[36]  N. Daigle,et al.  A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. , 1996, Development.

[37]  B. Sauer.  Manipulation of transgenes by site-specific recombination: use of Cre recombinase. , 1993, Methods in enzymology.

[38]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .