868 required for NC induction. In parallel, it may modify the Notch signaling functional readout by selectively repressing or activating some of its effectors. The observed repression of Hes5 may disrupt the oscillation of Notch activity that main- tains neuronal progenitors [63] forcing early cell fate commit- ment. The observed reduction of proliferation is consistent with early cell fate commitment, which combined with the Bmp-dependent repression of neuronal progenitor fates, may propel neuroepithelial cells toward NC fate. EMT in Development and Cancer and the Implication of Hox Genes Many of the factors that participate in the NC genetic cas- cade, are also involved in tumor progression and cancer cells share many characteristics with NC cells, particularly, regard- ing EMT. Premigratory NC cells and nonmetastatic tumor cells form an epithelium with a typical apical-basal polarity loss of which is a prerequisite for migration initiated with the loss of tight junctions located in the apical zone [92]. Occlu- din and claudins are components of tight junctions and their expression progressively decreases both in NC and tumor cells [93]. Interestingly, occludin and claudin 12 were repressed in ESC-derived neuroepithelial cells in response to Hoxb1 induction (Gouti and Gavalas, unpublished data). At the onset of tumor metastasis and NC migration and concur- rently with loss of cell polarity the proﬁle of cadherin-expres- sion changes. Consistent with inducing EMT electroporation of Hoxb1 results in loss of cell polarity illustrated by the loss of cadherin 6b and N-cadherin expression and upregulation of cadherin 7. Changes in N-cadherin and cadherin 7 expression are stronger in the dorsal half of the neural tube possibly reﬂecting the dependence of Hoxb1-induced NC and EMT on dorsal Bmp signals. Altered Hox gene expression has been associated with tumor progression [94]. HOXB7 and HOXB13 have been linked to increased instances of metasta- sis in breast and ovarian cancers and their overexpression in cell lines enhances many features of EMT [95, 96]. Here, we provided evidence that Hox genes can directly induce EMT in vivo in concert with Notch and Bmp signaling that have also been implicated in tumor progression. Thus, we propose that some Hox genes may be important players in EMT during tu- mor progression. REFERENCES 1 2 3 4 5 6 7 8 Dupin E, Creuzet S, Le Douarin NM. The contribution of the neural crest to the vertebrate body. Adv Exp Med Biol 2006;589:96–119. Crane JF, Trainor PA. Neural crest stem and progenitor cells. Annu Rev Cell Dev Biol 2006;22:267–286. Morales AV, Barbas JA, Nieto MA. 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Hox Genes and Neural Crest Speciﬁcation CONCLUSION Several studies have demonstrated the role of Hox genes in patterning NC cells, particularly in the cranial region of the body, but despite indications from loss-of-function studies that anterior Hox genes may participate in NC induction, direct evidence was missing. Dorsalization of ES-derived NS by dorsal morphogenetic signals resulted in strong upregula- tion of the key NC-inducing gene Msx1 selectively in Hoxb1þ but not Hoxb1 NS cells, suggesting that Hox genes may indeed participate in NC induction. We addressed this hypoth- esis by expressing Hoxb1 and other anterior Hox genes in the caudal neural tube of the developing chick embryo. We found that anterior Hox genes play a central role in NC cell speciﬁ- cation by rapidly inducing the key transcription factors Snail2 and Msx1/2 and mobilizing the complete NC speciﬁcation genetic program. 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