Abstract
The differentiated cell identities and structure of fully formed organs are generally stable after their development. In contrast, we report here that development of the C. elegans proximal somatic gonad (hermaphrodite uterus and spermathecae, and male vas deferens) can be redirected into intestine-like organs by brief expression of the ELT-7 GATA transcription factor. This process converts one developing organ into another and can hence be considered “transorganogenesis.” We show that, following pulsed ELT-7 expression, cells of the uterus activate and maintain intestine-specific gene expression and are transformed at the ultrastructural level to form an epithelial tube resembling the normal intestine formed during embryogenesis. Ubiquitous ELT-7 expression activates intestinal markers in many different cell types but only cells in the somatic gonad and pharynx appear to become fully reprogrammed. We found that ectopic expression of other endoderm-promoting transcription factors, but not muscle- or ectoderm- promoting transcription factors, redirects the fate of these organs, suggesting that pharyngeal and somatic gonad cells are specifically competent to adopt intestine identity. Although the intestine, pharynx, and somatic gonad are derived from distant cell lineages, they all express the PHA-4/FoxA transcription factor. While we found that post-embryonic PHA-4 is not necessary for pharynx or uterus reprogramming and PHA-4 is not sufficient in combination with ELT-7 to induce reprogramming in other cells types, knock down of PHA-4 during embryogenesis, which abolishes normal pharynx differentiation, prevents pharyngeal precursors from being reprogrammed into intestine. These results suggest that differentiated cell identity determines susceptibility to transdifferentiation and highlight the importance of cellular context in controlling competency for reprogramming.
Highlights
A major goal in the study of development is to understand how the history of a cell determines its commitment to a final identity
Cells of the C. elegans pharynx and intestine are distinct in cell lineage, morphology, function, and gene expression (Horner et al, 1998; Maduro and Rothman, 2002; Mango, 2007; Sommermann et al, 2010)
We found that transorganogenesis is not limited to the hermaphrodite proximal somatic gonad: the male vas deferens, which develops from the same cell lineage as the hermaphrodite somatic gonad (Kimble and Hirsh, 1979), undergoes striking transformation into an intestine-like organ in response to ELT-7 expression (Fig. 2D,E)
Summary
A major goal in the study of development is to understand how the history of a cell determines its commitment to a final identity. Differentiated cells can be reprogrammed into induced pluripotent stem cells (iPSCs) or directly converted into other differentiated cell types by forced expression of transcription factors (Tachibana et al, 1996; Takahashi and Yamanaka, 2006). Induced pluripotent stem cells (IPSCs) that have been obtained from many cell types more readily differentiate back into the lineage from which they were derived, evidence that the ancestral identity of a cell influences its subsequent redifferentiation (Marchetto et al, 2009; Hu et al, 2010). While much effort has been directed at reprogramming fibroblasts directly into distantly related cells (forced transdifferentiation), such as melanocytes (Tachibana et al, 1996) or neurons (Vierbuchen et al, 2010), the extent to which similar approaches can be applied to reprogram a wider variety of cell types remains unclear. Some cells from diverse embryonic origins can converge on similar identities, indicating that cell lineage, including germ layer origin, is not an inviolable determinant of final identity
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