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During development, neurons need to couple their robust axonal growth with their energetic balance. The mechanisms that regulate this coupling are largely unknown. Here we show that sensory neurons that lack Liver Kinase B1 (LKB1), a master regulator of energy homeostasis, exhibit reduced axonal growth and branching. Biochemical analysis of these LKB1 KO neurons revealed metabolic irregularities, manifested by axonal reduction in ATP levels. Genomic analysis uncovered downregulation in Efhd1 (EF-Hand Domain Family Member D1), a mitochondrial Ca2+-binding protein in the LKB1 KO sensory neurons. Strikingly, genetic ablation of Efhd1 caused a decrease in the axonal ATP levels and activation of the AMPK (AMP-activated protein kinase) pathway in sensory neurons. Moreover, we detected shortened mitochondria at the axonal growth cones and activation of the mitophagy regulator ULK (Unc-51 like autophagy activating kinase). Suggesting that Efhd1 is an important regulator of the axonal mitochondria. Notably, these metabolic dysfunctions were manifested by reduced axonal growth in vitro, and axonal branching defects and enhanced neuronal death in vivo. Overall, our work uncovers a new metabolic pathway that couples mitochondrial and axonal growth through Efhd1.

Stability of mRNA molecules is generally considered to be an intrinsic and constant feature of every distinct transcript. This study investigated the effect of transcription on the stabilities of multiple human and mouse mRNAs. We found that transcription positively regulates mRNA stability, rendering efficiently transcribed messengers less prone to degradation. Being independent of either translation or expression levels, this phenomenon is based exclusively on the co-transcriptionally deposited m6A modification, length of poly(A) tails, and the preferential activity of the CCR4-Not complex toward m6A-marked transcripts. Moreover, we demonstrate that upon large-scale transcriptional changes, such as during stress response or differentiation, the cell dynamically regulates its degradation machinery to buffer the global levels of mRNAs. We found this phenomenon to affect stabilities of virtually all tested mRNAs, thus providing transcription an additional regulatory pathway to globally impact mRNA stability. Overall, we conclude that transcription is a primary regulator of mRNA degradation in eukaryotic cells. We postulate that mRNA stability is a flexible epigenetic feature that is continuously and dynamically adjusted to transcriptional fluctuations in order to fine-tune gene expression in the ever-changing conditions.

In classic models of vision, vision proceeds in a hierarchical fashion, from low-level analysis (edges and lines) to figural processing (shapes and objects). Low-level processing determines high-level processing. Here, we show that shape processing determines basic visual processing as much as the other way around. For example, we presented a vernier stimulus and asked observers to indicate its offset direction. Performance strongly deteriorated when the vernier was surrounded by a square, in line with most models of vision. Surprisingly, performance improved when more squares were added. This improvement of performance can hardly be explained by classic models of vision, which predict a further deterioration of performance. We propose that shape interactions precede low-level processing in a recurrent fashion. Using high density EEG and trans-cranial magnetic stimulation (TMS), we show how good Gestalt emerges during recurrent, unconscious processing within 420ms. The outcome of this processing, i.e., the conscious percept, determines, paradoxically, what is usually referred to as early visual processing.