Left-right asymmetry in the light of TOR: An update on what we know so far

Abstract

The internal left-right (LR) asymmetry is a characteristic that exists throughout the animal kingdom from roundworms over flies and fish to mammals. Cilia, which are antenna-like structures protruding into the extracellular space, are involved in establishing LR asymmetry during early development. Humans who suffer from dysfunctional cilia often develop conditions such as heterotaxy, where internal organs appear to be placed randomly. As a consequence to this failure in asymmetry development, serious complications such as congenital heart defects (CHD) occur. The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has recently emerged as an important regulator regarding symmetry breaking. The mTOR pathway governs fundamental processes such as protein translation or metabolism. Its activity can be transduced by two complexes, which are called TORC1 and TORC2, respectively. So far, only TORC1 has been implicated with asymmetry development and appears to require very precise regulation. A number of recent papers provided evidence that dysregulated TORC1 results in alterations of motile cilia and asymmetry defects. In here, we give an update on what we know so far of mTORC1 in LR asymmetry development.

Keywords: Cilia; Heterotaxy; Left-right asymmetry; TORC1; Zebrafish.

Figure 1

Development of the temporal organ of laterality in zebrafish During gastrulation (6‐10 hpf) DFCs (in blue) migrate and eventually coalesce into a rosette‐like structure. By 4 ss, a simple, fluid filled vesicle has formed, in which the first cilia appear. Soon after, the cilia, which are asymmetrically distributed along the AP axis in the KV (Wang et al., 2012), start beating in a clockwise direction. Through that movement, a counterclockwise flow is induced, which is indispensable for the induction of laterality genes (blue bar). hpf, hours post fertilisation; ss, somite stage.

Figure 2

Key players of the mTOR complex1 cascade in LR asymmetry Cartoon depicting a simplified model of the TORC1‐dependent signalling pathway and its physiological outcome. Proteins, which have been associated with LR asymmetry are lined in red, whereas those that were shown to alter cilia size are additionally lined in blue. LKB1, liver kinase B1; AMPK, AMP‐activated protein kinase; TSC1/2, tuberous sclerosis 1/2; GSK3B, glycogen synthase kinase 3B; TORC1, target of rapamycin complex 1; GRK5, G protein‐coupled receptor kinase 5; ULK1, unc‐51 like autophagy activating kinase 1; Atg14, autophagy related 14; S6K1, S6 kinase 1; 4E‐BP1, Eukaryotic Translation Initiation Factor 4E Binding Protein 1; SREBP‐1, Sterol Regulatory Element‐Binding Protein 1; PPARγ, peroxisome proliferator‐activated receptor gamma.