MicroRNA-221 regulates chondrogenic differentiation through promoting proteosomal degradation of slug by targeting mdm2

In vertebrates, canonical Wnt-signaling controls posterior-neural cell lineage specification. Although Wnt-signaling to the neural plate is sufficient for posterior identity, the source and timing of this activity remain uncertain. Furthermore, critical molecular targets of this activity have not been defined. We utilized the advantages of the Xenopus embryo system to identify the endogenous Wnt activity and its role in controlling a critical downstream transcription factor, Meis3. Wnt3a is expressed in a specialized mesodermal domain: the paraxial dorsal–lateral mesoderm, which signals to overlying neuroectoderm. We show that Wnt3a is required in this region to activate Meis3 expression in adjacent neuroectoderm cells. Loss of zygotic Wnt3a in this region blocks Meis3 expression, triggering the subsequent loss of posterior neural fates. Over-expression of Meis3 protein is sufficient to rescue this phenotype. Moreover, neural caudalizing Wnt3a morphogenic activity requires functional Meis3 in the neural plate. ChIP and transgenic promoter analyses show that Meis3 is a direct target of Wnt β-catenin signaling. At later neurula stages, we show that Wnt3a and Meis3 act in a feedback loop in the neural plate, which is auto-regulated by Meis3. This suggests a new model for neural anterior–posterior patterning, in which Wnt3a from the paraxial mesoderm induces posterior cell fates via direct activation of a critical transcription factor in the overlying neural plate. This work reveals a core Wnt–Meis–Hox gene regulatory network controlling hindbrain formation. This mode of action is conserved in various developing systems throughout the Bilateria super phylum.