Individual cell types have characteristic sizes, suggesting that size sensing mechanisms may coordinate transcription, translation, and metabolism with cell growth rates. Two types of size-sensing mechanisms have been proposed: spatial sensing of the location or dimensions of a signal, subcellular structure or organelle; or titration-based sensing of the intracellular concentrations of key regulators. Here we propose that size sensing in animal cells combines both titration and spatial sensing elements in a dynamic mechanism whereby microtubule motor-dependent localization of RNA encoding importin β1 and mTOR, coupled with regulated local protein synthesis, enable cytoskeleton length sensing for cell growth regulation.
How can cells sense their own size to coordinate biosynthesis and metabolism with their growth needs? We recently proposed a motor-dependent bidirectional transport mechanism for axon length and cell size sensing, but the nature of the motor-transported size signals remained elusive. Here, we show that motor-dependent mRNA localization regulates neuronal growth and cycling cell size. We found that the RNA-binding protein nucleolin is associated with importin beta1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin beta1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin beta1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells.
Local signaling events at synapses or axon terminals must be communicated to the nucleus to elicit transcriptional responses. The lengths of neuronal processes pose a significant challenge for such intracellular communication. This challenge is met by mechanisms ranging from rapid signals encoded in calcium waves to slower macromolecular signaling complexes carried by molecular motors. Here we summarize recent findings on macromolecular signaling from the synapse to the nucleus, in comparison to those employed in injury signaling along axons. A number of common themes emerge, including combinatorial signal encoding by post-translational mechanisms such as differential phosphorylation and proteolysis, and conserved roles for importins in coordinating signaling complexes. Neurons may integrate ionic flux with motor-transported signals as a temporal code for synaptic plasticity signaling.
Neurons exhibit great size differences, and must coordinate biosynthesis rates in cell bodies with the growth needs of different lengths of axons. Classically, axon growth has been viewed mainly as a consequence of extrinsic influences. However, recent publications have proposed at least two different intrinsic axon growth-control mechanisms. We suggest that these mechanisms form part of a continuum of axon growth-control mechanisms, wherein initial growth rates are pre-programmed by transcription factor levels, and subsequent elongating growth is dependent on feedback from intrinsic length-sensing enabled by bidirectional motor-dependent oscillating signals. This model might explain intrinsic limits on elongating neuronal growth and provides a mechanistic framework for determining the connections between genome expression and cellular growth rates in neurons.
Size homeostasis is fundamental in cell biology, but it is not clear how large cells such as neurons can assess their own size or length. We examined a role for molecular motors in intracellular length sensing. Computational simulations suggest that spatial information can be encoded by the frequency of an oscillating retrograde signal arising from a composite negative feedback loop between bidirectional motor-dependent signals. The model predicts that decreasing either or both anterograde or retrograde signals should increase cell length, and this prediction was confirmed upon application of siRNAs for specific kinesin and/or dynein heavy chains in adult sensory neurons. Heterozygous dynein heavy chain 1 mutant sensory neurons also exhibited increased lengths both in vitro and during embryonic development. Moreover, similar length increases were observed in mouse embryonic fibroblasts upon partial downregulation of dynein heavy chain 1. Thus, molecular motors critically influence cell-length sensing and growth control.