Chicken Ovalbumin Upstream Promoter-Transcription Factor Members Repress Retinoic Acid-induced Cdx1 Expression

It is well established that Hox genes are key players in specifying positional identity along the anterior-posterior axis and are targets of diverse transcription factors implicated in axial patterning. Members of the CDX family (CDX1, -2, and -4) are among such effectors of Hox expression as pertains to vertebral patterning in the mouse. Cdx members are themselves targets of signaling molecules that are also implicated in axial patterning, including retinoic acid (RA) and certain members of Wnt and fibroblast growth factor families. In this regard, we have previously shown that, in the mouse, Cdx1 is directly regulated by RA at the late primitive streak stage (embryonic day (E) 7.5) through a RA response element in the proximal Cdx1 promoter. At E8.5, Cdx1 expression remains essentially limited to the posterior embryo. RA, however, is excluded from the caudal embryo at this later stage, but is found in a more anterior domain encompassing the prospective trunk region. These observations suggest the existence of a repressor mechanism that prevents expression of Cdx1 in these anterior domains of retinoid signaling at E8.5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element. Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded. Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo. It is well established that Hox genes are key players in specifying positional identity along the anterior-posterior axis and are targets of diverse transcription factors implicated in axial patterning. Members of the CDX family (CDX1, -2, and -4) are among such effectors of Hox expression as pertains to vertebral patterning in the mouse. Cdx members are themselves targets of signaling molecules that are also implicated in axial patterning, including retinoic acid (RA) and certain members of Wnt and fibroblast growth factor families. In this regard, we have previously shown that, in the mouse, Cdx1 is directly regulated by RA at the late primitive streak stage (embryonic day (E) 7.5) through a RA response element in the proximal Cdx1 promoter. At E8.5, Cdx1 expression remains essentially limited to the posterior embryo. RA, however, is excluded from the caudal embryo at this later stage, but is found in a more anterior domain encompassing the prospective trunk region. These observations suggest the existence of a repressor mechanism that prevents expression of Cdx1 in these anterior domains of retinoid signaling at E8.5. In the present study, we present evidence suggesting that chicken ovalbumin upstream promoter-transcription factor (COUP-TF) members antagonize RA-induced Cdx1 expression by competing with retinoid X receptor-retinoic acid receptor heterodimers for binding to the Cdx1 RA response element. Consistent with this, in situ hybridization analysis revealed that COUP-TFs are highly expressed in the anterior embryo in domains where Cdx1 transcripts are excluded. Together with other data, these findings suggest a model by which COUP-TF expression is induced by RA in the trunk region as a negative feedback mechanism to restrict Cdx1 expression to the caudal embryo. The Cdx family (Cdx1, -2, and -4) encode homeodomain transcription factors. A role for CDX1 and CDX2 in vertebral patterning has been clearly demonstrated by gene targeting studies. Cdx1–/– (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed and PubMed of the and anterior a of of these suggesting that gene Meyer B.I. and CDX2 to vertebral patterning at in through of Hox gene expression (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed Meyer B.I. Consistent with this, the vertebral in Cdx are of in certain Hox these vertebral are with a posterior in the anterior expression domains of Hox A of Hox also CDX binding (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed at of which have been demonstrated to in Cdx1 transcripts are at day RA, retinoic chicken ovalbumin upstream promoter-transcription RA response retinoic acid retinoid X RA, retinoic chicken ovalbumin upstream promoter-transcription RA response retinoic acid retinoid X in the and of the primitive streak B.I. Gruss P. and this expression is at through of expression is with the of Hox gene expression in the caudal have previously demonstrated that, in the mouse, Cdx1 is regulated at by retinoic acid (RA) present in the late primitive streak region through RA response element P. Cell. PubMed PubMed E8.5, Cdx1 expression is in the caudal embryo through Wnt signaling P. Meyer B.I. Gruss P. PubMed and P. Cell. PubMed RA, however, is in this region at this stage but is found in a more anterior domain in the prospective trunk V. PubMed this, Cdx1 transcripts are the of later expression in the and in the the existence of a mechanism that to Cdx1 expression in these more ovalbumin upstream promoter-transcription factors and are PubMed PubMed PubMed COUP-TFs have been shown to with receptor signaling including the Cell. PubMed Full Text PDF PubMed PubMed Cell. PubMed P. Cell. PubMed has been to by for with the binding domain of through with and for binding at response PubMed to with retinoid we COUP-TFs as negative of Cdx1 Consistent with such a in situ hybridization analysis in revealed that Cdx1 expression to where COUP-TF transcripts excluded. we found that COUP-TFs RA-induced of the Cdx1 in and that this the binding domain of also demonstrated that COUP-TFs the Cdx1 and from this element from a promoter. we found that expression of with of expression of Together these to a model in which RA expression of COUP-TFs in the trunk region of the embryo that to Cdx1 expression in the Cdx1 expression to the caudal of the Cdx1 a the Cdx1 have been previously P. Cell. PubMed and by a of The by of which encode the of the binding and in with in of at and the of of of expression and expression such that a of of The day with RA and for with by of and for as previously P. Cell. PubMed are as the from and are expressed as expression to in with and in of at with of and with RA as for In of with of expression and by and to and as for and for the of for as previously P. Cell. PubMed to the a Cdx1 of receptor binding and for binding have been previously P. Cell. PubMed In of in the binding for in situ hybridization as previously In A from Cdx1 COUP-TF from to the by through a and to a at in and that by at in and revealed by and Cdx1 of to COUP-TFs as negative of Cdx1 we the expression of in situ hybridization analysis revealed expression at in the anterior prospective with expression as at however, in the region. of expression also for expression of Cdx1 in the prospective to the of the caudal and in a region the posterior embryo at with expression to the and at and Cdx1 expression to where transcripts COUP-TFs excluded in with a role for COUP-TFs as negative of with of Cdx1 by RA and the Cdx1 COUP-TF members antagonize the of Cdx1 by RA, we with a gene P. Cell. 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Cell. PubMed a as a to the role of COUP-TFs as these factors RA through this element but with we the of a the of binding domain to Cdx1 demonstrated that, in to the Cdx1 is with the of this for binding by other members of the receptor V. P. PubMed the of the to RA-induced of the Cdx1 in in the to of the Cdx1 promoter. findings also with the expression from a P. Cell. 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PubMed have shown that COUP-TFs with of retinoic acid and receptor and PubMed PubMed A the of COUP-TF the Cdx1 suggesting that is implicated in this that are PubMed PubMed evidence for for binding from the that and and that the of the Cdx1 promoter. In this regard, the Cdx1 is to a receptor response and COUP-TF have been demonstrated to to such Cell. PubMed P. Cell. PubMed PubMed these a model COUP-TFs Cdx1 expression in the of RA by with heterodimers for binding to the Cdx1 to the primitive streak and Cdx1 is also expressed in the of the at and a with in the P. Gruss P. PubMed In this regard, the Cdx1 as a element in a Full Text PDF PubMed have also the of and transcripts along the and in the Cell. PubMed 1995; PubMed P. P. PubMed with present is to that negative by COUP-TFs also to the expression of Cdx1 in the the role of CDX1 in this is has been that in specifying identity along the anterior-posterior axis of the Meyer B.I. as has been demonstrated for CDX2 PubMed P. PubMed A in CDX1 by with CDX2 Meyer B.I. are in PubMed PubMed is a role for in vertebral patterning as by the of the and in the present is that this to of The and with expression also these transcription factors as has also been from gene targeting studies. for the vertebral in to the of of of RA vertebral patterning has been well Hox genes to RA, a limited have been demonstrated to have previously that Cdx1 as RA and Hox gene expression P. Cell. PubMed of by which Cdx1 expression is is to the vertebral patterning. The in the present to the model Cdx1 expression is induced by RA in the primitive streak region at At E8.5, RA in the Cdx1 expression is in the caudal embryo by Wnt signaling and P. Cell. PubMed expression of Cdx1 in the which is RA COUP-TF which to the by in a of Cdx1 transcripts to the caudal to Hox gene expression and patterning of the vertebral anterior-posterior RA Cdx1 at in the primitive streak region. is in this region at in the of RA a mechanism and At E8.5, retinoid signaling in the trunk region which of Cdx1 by RA in this The Cdx family (Cdx1, -2, and -4) encode homeodomain transcription factors. A role for CDX1 and CDX2 in vertebral patterning has been clearly demonstrated by gene targeting studies. Cdx1–/– (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed and PubMed of the and anterior a of of these suggesting that gene Meyer B.I. CDX1 and CDX2 to vertebral patterning at in through of Hox gene expression (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed Meyer B.I. Consistent with this, the vertebral in Cdx are of in certain Hox these vertebral are with a posterior in the anterior expression domains of Hox A of Hox also CDX binding (1.Subramanian V. Meyer B.I. Gruss P. Cell. 1995; 83: 641-653Abstract Full Text PDF PubMed at of which have been demonstrated to in Cdx1 transcripts are at day RA, retinoic chicken ovalbumin upstream promoter-transcription RA response retinoic acid retinoid X RA, retinoic chicken ovalbumin upstream promoter-transcription RA response retinoic acid retinoid X in the and of the primitive streak B.I. Gruss P. and this expression is at through of expression is with the of Hox gene expression in the caudal embryo. have previously demonstrated that, in the mouse, Cdx1 is regulated at by retinoic acid (RA) present in the late primitive streak region through RA response element P. Cell. PubMed PubMed E8.5, Cdx1 expression is in the caudal embryo through Wnt signaling P. Meyer B.I. Gruss P. PubMed and P. Cell. PubMed RA, however, is in this region at this stage but is found in a more anterior domain in the prospective trunk V. PubMed this, Cdx1 transcripts are the of later expression in the and in the the existence of a mechanism that to Cdx1 expression in these more ovalbumin upstream promoter-transcription factors and are PubMed PubMed PubMed COUP-TFs have been shown to with receptor signaling including the Cell. PubMed Full Text PDF PubMed PubMed Cell. PubMed P. Cell. PubMed has been to by for with the binding domain of through with and for binding at response PubMed to with retinoid we COUP-TFs as negative of Cdx1 Consistent with such a in situ hybridization analysis in revealed that Cdx1 expression to where COUP-TF transcripts excluded. we found that COUP-TFs RA-induced of the Cdx1 in and that this the binding domain of also demonstrated that COUP-TFs the Cdx1 and from this element from a promoter. we found that expression of with of expression of Together these to a model in which RA expression of COUP-TFs in the trunk region of the embryo that to Cdx1 expression in the Cdx1 expression to the caudal embryo. of the Cdx1 a the Cdx1 have been previously P. Cell. PubMed and by a of The by of which encode the of the binding and in with in of at and the of of of expression and expression such that a of of The day with RA and for with by of and for as previously P. Cell. PubMed are as the from and are expressed as expression to in with and in of at with of and with RA as for In of with of expression and by and to and as for and for the of for as previously P. Cell. PubMed to the a Cdx1 of receptor binding and for binding have been previously P. Cell. PubMed In of in the binding for in situ hybridization as previously In A from Cdx1 COUP-TF from to the by through a and to a at in and that by at in and revealed by of the Cdx1 a the Cdx1 have been previously P. Cell. PubMed and by a of The by of which encode the of the binding and in with in of at and the of of of expression and expression such that a of of The day with RA and for with by of and for as previously P. Cell. PubMed are as the from and are expressed as expression to in with and in of at with of and with RA as for In of with of expression and by and to and as for and for the of for as previously P. Cell. PubMed to the a Cdx1 of receptor binding and for binding have been previously P. Cell. PubMed In of in the binding for In in situ hybridization as previously In A from Cdx1 COUP-TF from to the by through a and to a at in and that by at in and revealed by and Cdx1 of to COUP-TFs as negative of Cdx1 we the expression of in situ hybridization analysis revealed expression at in the anterior prospective with expression as at however, in the region. of expression also for expression of Cdx1 in the prospective to the of the caudal and in a region the posterior embryo at with expression to the and at and Cdx1 expression to where transcripts COUP-TFs excluded in with a role for COUP-TFs as negative of with of Cdx1 by RA and the Cdx1 COUP-TF members antagonize the of Cdx1 by RA, we with a gene P. Cell. PubMed the of Cdx1 including the and the in the of RA shown in RA in of with findings P. Cell. PubMed of the with of expression in a of this have been shown to repressor through including for of response COUP-TFs to the Cdx1 this from with with a of the Cdx1 from with as a heterodimers have been shown to to this element P. Cell. PubMed The in that and a with the Cdx1 and that to the The of in by the and of binding established by with and a Cdx1 and binding and to demonstrated that COUP-TFs directly to the Cdx1 this Cdx1 we the of COUP-TFs RA from a the Cdx1 shown in and RA-induced from this by to of the of Cdx1 by RA P. Cell. PubMed a as a to the role of COUP-TFs as these factors RA through this element but with we the of a the of binding domain to Cdx1 demonstrated that, in to the Cdx1 is with the of this for binding by other members of the receptor V. P. PubMed the of the to RA-induced of the Cdx1 in in the to of the Cdx1 promoter. findings also with the expression from a P. Cell. 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Cell. PubMed the of Cdx1 including the and the in the of RA shown in RA in of with findings P. Cell. PubMed of the with of expression in a of this COUP-TFs have been shown to repressor through including for of response COUP-TFs to the Cdx1 this from with with a of the Cdx1 from with as a heterodimers have been shown to to this element P. Cell. PubMed The in that and a with the Cdx1 and that to the The of in by the and of binding established by with and a Cdx1 and binding and to The demonstrated that COUP-TFs directly to the Cdx1 this Cdx1 we the of COUP-TFs RA from a the Cdx1 shown in and RA-induced from this by to of the of Cdx1 by RA P. Cell. PubMed a as a to the role of COUP-TFs as these factors RA through this element but with we the of a the of binding domain to Cdx1 demonstrated that, in to the Cdx1 is with the of this for binding by other members of the receptor V. P. 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PubMed have shown that COUP-TFs with of retinoic acid and receptor and PubMed PubMed A the of COUP-TF the Cdx1 suggesting that is implicated in this that are PubMed PubMed evidence for for binding from the that and and that the of the Cdx1 promoter. In this regard, the Cdx1 is to a receptor response and COUP-TF have been demonstrated to to such Cell. PubMed P. Cell. PubMed PubMed these a model COUP-TFs Cdx1 expression in the of RA by with heterodimers for binding to the Cdx1 to the primitive streak and Cdx1 is also expressed in the of the at and a with in the P. Gruss P. PubMed In this regard, the Cdx1 as a element in a Full Text PDF PubMed have also the of and transcripts along the and in the Cell. PubMed 1995; PubMed P. P. PubMed with present is to that negative by COUP-TFs also to the expression of Cdx1 in the the role of CDX1 in this is has been that in specifying identity along the anterior-posterior axis of the Meyer B.I. as has been demonstrated for CDX2 PubMed P. PubMed A in CDX1 by with CDX2 Meyer B.I. are in PubMed PubMed is a role for in vertebral patterning as by the of the and in the present is that this to of The and with expression also these transcription factors as has also been from gene targeting studies. for the vertebral in to the of of of RA vertebral patterning has been well Hox genes to RA, a limited have been demonstrated to have previously that Cdx1 as RA and Hox gene expression P. Cell. PubMed of by which Cdx1 expression is is to the vertebral patterning. The in the present to the model Cdx1 expression is induced by RA in the primitive streak region at At E8.5, RA in the Cdx1 expression is in the caudal embryo by Wnt signaling and P. Cell. PubMed expression of Cdx1 in the which is RA COUP-TF which to the by in a of Cdx1 transcripts to the caudal to Hox gene expression and patterning of the vertebral anterior-posterior The in this evidence that COUP-TFs antagonize the of Cdx1 by The of the to this that COUP-TF binding is to this also the that this from the the binding domains of COUP-TFs and as such a mechanism COUP-TF binding to Cell. PubMed have shown that COUP-TFs with of retinoic acid and receptor and PubMed PubMed A the of COUP-TF the Cdx1 suggesting that is implicated in this that are PubMed PubMed evidence for for binding from the that and and that the of the Cdx1 promoter. In this regard, the Cdx1 is to a receptor response and COUP-TF have been demonstrated to to such Cell. PubMed P. Cell. PubMed PubMed these a model COUP-TFs Cdx1 expression in the of RA by with heterodimers for binding to the Cdx1 In to the primitive streak and Cdx1 is also expressed in the of the at and a with in the P. Gruss P. PubMed In this regard, the Cdx1 as a element in a Full Text PDF PubMed have also the of and transcripts along the and in the Cell. PubMed 1995; PubMed P. P. PubMed with present is to that negative by COUP-TFs also to the expression of Cdx1 in the the role of CDX1 in this is has been that in specifying identity along the anterior-posterior axis of the Meyer B.I. as has been demonstrated for CDX2 PubMed P. PubMed A in CDX1 by with CDX2 Meyer B.I. COUP-TFs are in PubMed PubMed is a role for in vertebral patterning as by the of the and in the present is that this to of The and with expression also these transcription factors as has also been from gene targeting studies. for the vertebral in to the of of The of RA vertebral patterning has been well Hox genes to RA, a limited have been demonstrated to have previously that Cdx1 as RA and Hox gene expression P. Cell. PubMed of by which Cdx1 expression is is to the vertebral patterning. The in the present to the model Cdx1 expression is induced by RA in the primitive streak region at At E8.5, RA in the Cdx1 expression is in the caudal embryo by Wnt signaling and P. Cell. PubMed expression of Cdx1 in the which is RA COUP-TF which to the by in a of Cdx1 transcripts to the caudal to Hox gene expression and patterning of the vertebral anterior-posterior for the COUP-TF and for and for to this

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