Xenopus Meis3 protein lies at a nexus downstream to Zic1 and Pax3 proteins, regulating multiple cell-fates during early nervous system development

Abstract

In Xenopus embryos, XMeis3 protein activity is required for normal hindbrain formation. Our results show that XMeis3 protein knock down also causes a loss of primary neuron and neural crest cell lineages, without altering expression of Zic, Sox or Pax3 genes. Knock down or inhibition of the Pax3, Zic1 or Zic5 protein activities extinguishes embryonic expression of the XMeis3 gene, as well as triggering the loss of hindbrain, neural crest and primary neuron cell fates. Ectopic XMeis3 expression can rescue the Zic knock down phenotype. HoxD1 is an XMeis3 direct-target gene, and ectopic HoxD1 expression rescues cell fate losses in either XMeis3 or Zic protein knock down embryos. FGF3 and FGF8 are direct target genes of XMeis3 protein and their expression is lost in XMeis3 morphant embryos. In the genetic cascade controlling embryonic neural cell specification, XMeis3 lies below general-neuralizing, but upstream of FGF and regional-specific genes. Thus, XMeis3 protein is positioned at a key regulatory point, simultaneously regulating multiple neural cell fates during early vertebrate nervous system development.

Mesodermal Wnt signaling organizes the neural plate via Meis3

“…We showed that Meis3 is required for Xenopus posterior neural cell fate specification. In the absence of Meis3 activity, embryos lose numerous posterior neural cell fates, such as of the hindbrain, primary neuron and neural crest, but not the spinal cord; the forebrain is posteriorly expanded; pan-neural marker expression is normal (Dibner et al, 2001;Gutkovich et al, 2010). We also showed that Meis3 induces posterior neural cell fates noncell autonomously, perhaps by way of other secreted factors (Aamar and Frank, 2004).…”

Distinct and redundant expression and transcriptional diversity of MEIS gene paralogs during chicken development

“…Although Meis3 seems to have a more restricted expression pattern than the other two Meis genes in mouse, Xenopus, and zebrafish (Waskiewicz et al, 2001;Ng et al, 2009), it has been implicated in several developmental processes in these species (Dibner et al, 2001(Dibner et al, , 2004Aamar and Frank, 2004;diIorio et al, 2007;Manfroid et al, 2007;Elkouby et al, 2010;Gutkovich et al, 2010). However, these roles could represent evolutionary novelties or cooptions in these lineages or, alternatively, could have been taken over by the other Meis genes in birds.…”

“…Xenopus Meis genes have been thoroughly studied during gastrulation. XMeis3 is expressed in the caudal neural plate from early-mid neurula stages onward and can induce hindbrain cell fates (Salzberg et al, 1999;Elkouby et al, 2010;Gutkovich et al, 2010). Because the chicken has no Meis3, this function may be carried out in this species by Meis1/Meis2 during early neural plate and neural crest formation.…”

“…Finally, mouse Meis2 is expressed from the rh1-rh2 boundary down to the caudalmost rhombomeres (Cecconi et al, 1997;Oulad-Abdelghani et al, 1997). Therefore, there is some disagreement in the reported segmental expression of Meis genes in vertebrates, possibly due in part to different criteria for counting rhombomeres, but all authors have concluded that Meis family genes are essential for the specification of hindbrain rhombomeres (Jacobs et al, 1999;Ferreti et al, 2000;Dibner et al, 2001Dibner et al, , 2004Choe et al, 2002;Wassef et al, 2008;Elkouby et al, 2010;Gutkovich et al, 2010).…”

“…Therefore, by regulating the expression of each gene, and the proportions between them and the several splicing isoforms (also known to have different properties), each cell will have a specific value or potential of MEIS activity and response to various cellular signals (Huang et al, 2005), given by their specific MEIS protein composition. Because Meis is known to regulate key processes such as cell proliferation and fate specification (Salzberg et al, 1999;Mercader et al, 2005;Bessa et al, 2008), as well as patterning and cell differentiation Heine et al, 2009;Elkouby et al, 2010;Gutkovich et al, 2010), this is likely to allow a more complex and gradual regulation of ontogenesis in vertebrates, compared with invertebrates with a single Meis gene. Importantly, these principles are likely to apply to many important developmental genes in vertebrates, for which different paralogs, often showing AS, are known to play slightly-but crucially-different roles during vertebrate development (e.g., Pax3 and Pax7 in pretectum patterning, Ferran et al, 2007).…”