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Dev Biol
2012 Jul 15;3672:163-77. doi: 10.1016/j.ydbio.2012.04.033.
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The Mix family of homeobox genes--key regulators of mesendoderm formation during vertebrate development.
Pereira LA
,
Wong MS
,
Mei Lim S
,
Stanley EG
,
Elefanty AG
.
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The Mix/Bix family of paired-like homeobox genes encode evolutionarily conserved, sequence specific, DNA-binding transcription factors that have been implicated in the co-ordination of gene expression, axis formation and cell fate determination during gastrulation in vertebrates. When mutated, these genes give rise to dramatic phenotypes in amphibians, zebrafish and mice, that can be traced back to defects in the formation and specification of mesoderm and endoderm. We review here the biochemical properties of the Mix/Bix proteins and summarise genetic, molecular and embryological studies of Mix/Bix function in mesendoderm development. We emphasise recent data generated using embryonic stem cell differentiation systems that have provided important new insights into Mix/Bix function and the biological roles of these proteins in regulating the earliest phases of vertebrate development.
Fig. 2. Expression of Mixl1 in the developing mouse embryo. Regions of Mixl1 expression are marked in green (A) prior to gastrulation at day 5.5 in the visceral endoderm, (B) during gastrulation at day 7.0 in the primitive streak, (C) after gastrulation at day 9.5 in the tail bud. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 3. Cell lineage relationships in the mammalian embryo and their regulation by the BMP and Activin/nodal signaling pathways and the Mixl1 transcription factor. The colour scheme reflects the graded BMP/nodal signalling along the primitive streak that induces and patterns mesoderm and endoderm. Activation of BMP or Activin receptors leads to phopshorylation and nuclear translocation of heterodimeric Smad proteins that form activating complexes on the Mixl1 promoter in combination with proteins including FoxH1 or FoxH3. The inclusion of Eomes in these complexes is not yet confirmed.
Fig. 4. A simplified model of the Mixl1 genetic network controlling events surrounding primitive streak formation and the subsequent patterning of emerging mesendoderm in the mouse. Mixl1 activates transcription of a number of genes involved in mesoderm and endoderm development including Pdgfrα, Flk1 and Cxcr4 (Pereira et al., 2012) and Gsc, Sox17 and Cdh1 (E-cad) (Danilov et al., 1998, Izumi et al., 2007, Lim et al., 2009, Zhang et al., 2009). At least in the case of Gsc and Pdgfrα, it has been shown that Brachyury binds to promoter-bound Mixl1 to inhibit this function (Pereira et al., 2011). This is consistent with a negative feedback loop involving Mixl1 and Gsc that opposes Brachyury during mesendoderm differentiation. Dashed lines indicate that occupation of the promoter by Mixl1 has not yet been demonstrated.
