Increasing evidence suggests that miRNAs play important regulatory roles in the nervous system. However, the molecular mechanisms of how specific miRNAs affect neuronal development and functions remain less well understood. In the present study, we provide evidence that the conserved microRNA miR-210 regulates lipid metabolism and prevents neurodegeneration in the Drosophila retina. miR-210 is specifically expressed in the photoreceptor neurons and other sensory organs. Genetic deletion of miR-210 leads to lipid droplet accumulation and photoreceptor degeneration in the retina. These effects are associated with abnormal activation of the Drosophila sterol regulatory element-binding protein signaling. We further identify the acetyl-coenzyme A synthetase (ACS) as one functionally important target of miR-210 in this context. Reduction of ACS in the miR-210 mutant background suppresses the neurodegeneration defects, suggesting that miR-210 acts through regulation of the ACS transcript. Together, these results reveal an unexpected role of miR-210 in controlling lipid metabolism and neuronal functions.

Edited by Mike Shipston Atg101 is an autophagy-related gene identified in worms, flies, mice, and mammals, which encodes a protein that functions in autophagosome formation by associating with the ULK1-Atg13-Fip200 complex. In the last few years, the critical role of Atg101 in autophagy has been well-established through biochemical studies and the determination of its protein structure. However, Atg101's physiological role, both during development and in adulthood, remains less understood. Here, we describe the generation and characterization of an Atg101 lossof-function mutant in Drosophila and report on the roles of Atg101 in maintaining tissue homeostasis in both adult brains and midguts. We observed that homozygous or hemizygous Atg101 mutants were semi-lethal, with only some of them surviving into adulthood. Both developmental and starvation-induced autophagy processes were defective in the Atg101 mutant animals, and Atg101 mutant adult flies had a significantly shorter lifespan and displayed a mobility defect. Moreover, we observed the accumulation of ubiquitin-positive aggregates in Atg101 mutant brains, indicating a neuronal defect. Interestingly, Atg101 mutant adult midguts were shorter and thicker and exhibited abnormal morphology with enlarged enterocytes. Detailed analysis also revealed that the differentiation from intestinal stem cells to enterocytes was impaired in these midguts. Cell type-specific rescue experiments disclosed that Atg101 had a function in enterocytes and limited their growth. In summary, the results of our study indicate that Drosophila Atg101 is essential for tissue homeostasis in both adult brains and midguts. We propose that Atg101 may have a role in age-related processes. Autophagy (macroautophagy) is a process in which cytoplasmic materials, including organelles and macromolecules, are delivered to and degraded in the lysosome (1-4). As a major intracellular degradation system, autophagy plays important roles in development, tissue homeostasis, and aging (5-7). Defects in the autophagy pathway cause various human diseases, such as cancer and neurodegenerative diseases (8-10). Genetic studies from budding yeast have identified more than 30 Atg genes, which function at various steps during autophagy (2, 3, 11). Most of these genes are highly conserved from yeast to mammals (3, 11). Among them, the Atg1 complex acts at the initiation stage of autophagy functioning as a scaffold for the recruitment of downstream Atg 2 proteins to the preautophagosomal structure (4, 11-13). The yeast Atg1 complex consists of Atg1, Atg13, Atg17, Atg29, and Atg31, and its mammalian counterpart is composed of ULK1 (or ULK2), Atg13, FIP200 (also known as RB1CC1) and Atg101 (4, 11-13). Mammalian ULK1 and ULK2 are homologs of Atg1 (13). FIP200 is generally considered as a homolog of yeast Atg11 and Atg17 (13). Homologs of Atg29 and Atg31 are not found in higher eukaryotes (13). In contrast, Atg101 is present in most eukaryotes, with the exception of budding yeast (13). It has been proposed that the regu...

Adult progenitor cells in the trachea of Drosophila larvae are activated and migrate out of niches when metamorphosis induces tracheal remodeling. Here we show that in response to metabolic deficiency in decaying tracheal branches, signaling by the insulin pathway controls the progenitor cells by regulating Yorkie (Yki)-dependent proliferation and migration. Yki, a transcription coactivator that is regulated by Hippo signaling, promotes transcriptional activation of cell cycle regulators and components of the extracellular matrix in tracheal progenitor cells. These findings reveal that regulation of Yki signaling by the insulin pathway governs proliferation and migration of tracheal progenitor cells, thereby identifying the regulatory mechanism by which metabolic depression drives progenitor cell activation and cell division that underlies tracheal remodeling.

The Notch signaling pathway is highly conserved across different animal species and plays crucial roles in development and physiology. Regulation of Notch signaling occurs at multiple levels in different tissues and cell types. Here, we show that the histone deacetylase HDAC1 acts as a positive regulator of Notch signaling during Drosophila wing development. Depletion of HDAC1 causes wing notches on the margin of adult wing. Consistently, the expression of Notch target genes is reduced in the absence of HDAC1 during wing margin formation. We further provide evidence that HDAC1 acts upstream of Notch activation. Mechanistically, we show that HDAC1 regulates Notch protein levels by promoting Notch transcription. Consistent with this, the HDAC1-associated transcriptional co-repressor Atrophin (Atro) is also required for transcriptional activation of Notch in the wing disc. In summary, our results demonstrate that HDAC1 positively regulates Notch signaling and reveal a previously unidentified function of HDAC1 in Notch signaling.