Developemental plasticity and its loss during embryogenesis

Embryonic cells are born pluripotent but over time their developmental choices become restricted, and they begin to differentiate. This transition occurs in other animals, where stem cells or early embryonic cells are developmentally plastic, but their descendants ultimately commit to a particular cell fate. However, unlike cultured ES cells, for example, embryonic cells are pluripotent only for a brief period, and loss of plasticity is precisely regulated during development. What processes establish the pluripotent state? And what mechanisms govern the transition from pluripotency to cell-fate restriction? As described below, the C. elegans embryo is a powerful system to address these questions because the stages of plasticity vs. commitment are well defined temporally. We have used expression profiling and in vivo imaging to characterize C. elegans embryos as they transit from a developmentally plastic state to cell-fate restriction (Kiefer et al., Developmental Biology, 2007, Yuzyuk et al., Developmental Cell, 2009). Our experiments have set the stage for screens to identify genes that maintain developmental plasticity and genes that mediate its loss.

When do embryonic cells commit to a cell fate?

Somatic cells of the C. elegans embryo acquire different cellular characteristics that can be distinguished morphologically and molecularly by the two-cell stage. Traditionally, these differences were interpreted to mean that cell fates were determined very early. However, four observations suggest that somatic blastomeres from early embryos are developmentally plastic, and that plasticity is lost only during mid-gastrulation. First, prior to gastrulation (≤2E or Endodermal stage, ~28 cells), most blastomeres contribute to diverse cell types, whereas 2-3 cell divisions later (8E-16E stage, ~100-200 cells), cells typically produce descendants that contribute to only a single tissue or organ. Second, embryonic blastomeres adopt alternative fates when C. elegans developmental regulatory transcription factors are expressed ubiquitously (the Cell Fate Challenge Assay). The conversion is dramatic, such that a blastomere fated to give rise to neurons or skin, for example, can be converted into gut or muscle. This response is lost by the 8E-16E stage, and many cells fail to adopt alternate fates when challenged with an ectopic regulator. Third, signaling by the Notch and wnt pathways is important to establish many cell fates within the embryo. Thus, the reproducible cell lineage reflects, in part, reproducible cell signaling to cells with uncommitted fates. Fourth, developmental regulatory transcription factors have been identified, and those that function before the 8E stage often lead to cell fate transformations when mutated. Many developmental transcription factors that function after the 8E stage have subtler phenotypes involving morphogenesis, differentiation or fate changes between related cell types (Mango, 2007). These four observations suggest that C. elegans embryonic blastomeres are developmentally plastic, and that this characteristic is lost during gastrulation.

The discovery that mis-expression of developmental transcription factors can alter cell identity in early C. elegans embryos, described below, implicates transcriptional regulatory mechanisms for developmental plasticity and its loss. The factors that mediate these regulatory events are unknown, and we have initiated screens to uncover genes involved in the transition from plasticity to cell fate restriction. We are particularly interested in exploring the roles of nuclear organization and chromatin architecture in these events.

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