Academic journal article Genetics

A Regulatory Module Controlling Pharyngeal Development and Function in Caenorhabditis Elegans

Academic journal article Genetics

A Regulatory Module Controlling Pharyngeal Development and Function in Caenorhabditis Elegans

Article excerpt

ABSTRACT In Caenorhabditis elegans, the differentiation and morphogenesis of the foregut are controlled by several transcriptional regulators and cell signaling events, and by PHA-1, an essential cytoplasmic protein of unknown function. Previously we have shown that LIN-35 and UBC-18-ARI-1 contribute to the regulation of pha-1 and pharyngeal development through the Zn-finger protein SUP-35/ZTF-21. Here we characterize SUP-37/ZTF-12 as an additional component of the PHA-1 network regulating pharyngeal development. SUP-37 is encoded by four distinct splice isoforms, which contain up to seven C2H2 Zn-finger domains, and is localized to the nucleus, suggesting a role in transcription. Similar to sup-35, sup-37 loss-of-function mutations can suppress both LOF mutations in pha-1 as well as synthetic-lethal double mutants, including lin-35; ubc-18, which are defective in pharyngeal development. Genetic, molecular, and expression data further indicate that SUP-37 and SUP-35 may act at a common step to control pharyngeal morphogenesis, in part through the transcriptional regulation of pha-1. Moreover, we find that SUP-35 and SUP-37 effect pharyngeal development through a mechanism that can genetically bypass the requirement for pha-1 activity. Unlike SUP-35, SUP-37 expression is not regulated by either the LIN-35 or UBC-18-ARI-1 pathways. In addition, SUP-37 carries out two essential functions that are distinct from its role in regulating pharyngeal development with SUP-35. SUP-37 is required within a subset of pharyngeal muscle cells to facilitate coordinated rhythmic pumping and in the somatic gonad to promote ovulation. These latter observations suggest that SUP-37 may be required for the orchestrated contraction of muscle cells within several tissues.

ORGAN development is a complex process that is dependent on the tight spatiotemporal coordination of signaling networks, transcription factors, and effectors of cellular morphogenesis. In Caenorhabditis elegans, the foregut, which includes the buccal cavity, pharynx, and intestinal valve cells, has proven to be a powerful model for studies of the molecular mechanisms controlling organogenesis (Mango 2007, 2009). Although containing only 95 nuclei in the adult, the foregut is composed of seven distinct but functionally integrated cell types, which arise from diverse embryonic lineages (Albertson and Thomson 1976; Sulston et al. 1983). Furthermore, through autonomous control, the pharynx is capable of producing a rapid and regular pumping action that is essential for the ingestion and mechanical breakdown of food.

LIN-35/Rb, the C. elegans retinoblastoma-family ortholog, and UBC-18/UBCH7-ARI-1/AR1H1, a conserved E2-E3 ubiquitin-modification complex, function redundantly to control an early step of pharyngeal morphogenesis, termed reorientation (Fay et al. 2003; Qiu and Fay 2006). At this stage during normal development, the anteriormost cells of the pharyngeal primordium change from a radial configuration (with alignment along the rostrocaudal axis) to a parallel orientation, relative to the dorsoventral axis of the embryo (Portereiko and Mango 2001). At the same time, the apicobasal polarities of the leading anterior cells shiftfrom 30° to 90° to align their axes with the dorsoventral axis. These morphological changes ultimately facilitate the formation of a contiguous epithelial tube composed of pharyngeal cells and cells of the future buccal cavity (mouth). Misexecution of this step leads to a failure of the pharynx to attach to the buccal cavity (the Pun phenotype, for Pharynx unattached), together with concomitant defects in pharyngeal elongation (Fay et al. 2003; Portereiko et al. 2004).

We recently proposed a mechanism to account for the role of LIN-35 and UBC-18-ARI-1 in pharyngeal development (Mani and Fay 2009). Specifically, LIN-35 and UBC- 18-ARI-1 mutually inhibit the expression of SUP-35/ZTF-21, a Zn-finger protein. In the case of LIN-35, repression of SUP-35 occurs at the level of transcription and is carried out in conjunction with members of an evolutionarily conserved transcriptional repressor complex that contains E2F (Fay et al. …

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