Academic journal article Genetics

Autophagy Genes Unc-51 and Bec-1 Are Required for Normal Cell Size in Caenorhabditis Elegans

Academic journal article Genetics

Autophagy Genes Unc-51 and Bec-1 Are Required for Normal Cell Size in Caenorhabditis Elegans

Article excerpt

ABSTRACT

Here we show that in the nematode Caenorhabditis elegans mutational inactivation of two autophagy genes unc-51/atg1 and bec-1/atg6/beclin1 results in small body size without affecting cell number. Furthermore, loss-of-function mutations in unc-51 and bec-1 suppress the giant phenotype of mutant animals with aberrant insulin-like growth factor-1 (insulin/IGF-1) or transforming growth factor-β (TGF-β) signaling. This function for unc-51 and bec-1 in cell size control and their interaction with these two growth modulatory pathways may represent a link between the hormonal and nutritional regulation of cell growth.

IN multicellular organisms, the regulation of cell size is intimately linked to nutrient and growth factor availability and requires a well-controlled balance between macromolecule synthesis and degradation (KLIONSKY and EMR 2001; SAUCEDO and EDGAR 2002; OLDHAM and HAFEN 2003; DANIELPOUR and SONG 2005; LEEVERS and MCNEILL 2005). Cells divide only after they reach a critical size. Thus, cell growth is a prerequisite of cell proliferation and may be dysregulated in human malignancies. The insulin-like growth factor-1 (insulin/IGF-1) and transforming growth factor-b (TGF-β) signaling cascades are known as major regulatory systems for cell growth, proliferation, and differentiation (SALTIEL and KAHN 2001; DERYNCK and ZHANG 2003; OLDHAM and HAFEN 2003). However, little is known about cellular pathways that mediate these processes.

In Caenorhabditis elegans, both insulin/IGF-1 and TGF-β signaling pathways affect body length by controlling cell size (KRISHNA et al. 1999; SUZUKI et al. 1999; MORITA et al. 1999, 2002; MCCULLOCH and GEMS 2003). For example, loss-of-function mutations in the gene daf-2, which encodes the nematode IGF-1 receptor, extend body length, compared to the wild type (MCCULLOCH and GEMS 2003). The type I TGF-β receptor SMA-6 also influences body size in nematodes (KRISHNA et al. 1999). SMA-6 is activated by the growth factor DBL-1 and represses the expression of the PR-related protein LON-1, which is a novel negative regulator of cell growth (SUZUKI et al. 1999; MORITA et al. 1999, 2002). Mutations that eliminate the activity of LON-1 increase body length by 1.5-fold, whereas animals with elevated DBL-1 activity are also longer than the wild type.

The insulin/IGF-1 and TGF-β hormonal systems also control reproductive growth in this organism (Riddle and Albert 1997). Mutant nematodes with decreased DAF-2/IGF-1 receptor activity enter into a state of developmental diapause called dauer, which is an arrested larval form specialized to survive unfavorable conditions. In addition, mutations that inactivate the type I and type II TGF-β receptors, DAF-1 and DAF-4, respectively, result in constitutive dauer development independently of environmental cues (ESTEVEZ et al. 1993; GUNTHER et al. 2000). It was shown that dauer development in insulin/IGF-1- and TGF-β-signaling mutant nematodes requires the function of autophagy genes, and that normal dauer morphogenesis is associated with increased autophagy (MELÉNDEZ et al. 2003). Autophagy is a highly regulated cellular pathway used by eukaryotic cells to degrade parts of their contents during development and to survive nutrient deprivation (KLIONSKY and EMR 2001). Autophagic degradation of cytosolic materials is a major route for turnover of cellular macromolecules and organelles, in particular proteins and mitochondria. In this study, we investigate whether unc-51 and bec-1, which are mutationally characterized C. elegans autophagy genes, are required for maintaining normal cell size.

The wild-type C. elegans strains display a characteristic body length of 1.2 mm (Brenner 1974). We examined unc-51 loss-of-function mutant nematodes at a well-de- fined developmental stage (see Table 1) and found that they show a marked shortening in mean body size. For example, body length at the young adult stage was 0.89 ± 0.04 mm in unc-51(e369) mutants vs. …

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