Retinoic Acid Induces Stage-specific Repatterning of the Rostral Central Nervous System

We had previously reported that in gastrulating mouse embryos retinoic acid (RA) induces morphological as well molecular alterations strictly depending on the time of administration. In particular, embryos treated with RA at the mid-late streak stage share reduction of the rostral central nervous system (CNS) and increase of the hindbrain. In the same embryos, loss of the forebrain-expressed genes, such as Emx1, Emx2, and Dlx1, and rostral ectopic expression of the Hoxb-1 gene suggest an antero-posterior (A/P) ordered repatterning of the fore-, mid-, and hindbrain regions. Several genes, such as Pax-2, Wnt-1, En-2, and En-1, are involved in the establishment of midbrain and rostral hindbrain regional identities and boundaries. We report that these genes become coordinately anteriorized only in embryos treated with RA at the late streak stage. Moreover, in the hindbrain of the same embryos, at 8.5 days post coitum (dpc), Wnt-1 and Pax-2 are rostrally induced all along the neural plate. Considering that forebrain markers are repressed in embryos treated with RA at the same time, these findings strongly support the idea that RA administration at the late streak stage induces an ordered repatterning of the rostral CNS, possibly altering the A/P nature of mesendodermal inductive signals.