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1.
Nat Commun ; 15(1): 3330, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38684656

ABSTRACT

Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in gene expression. However, how gene expression is regulated differently to ensure meiotic prophase completion in males remains elusive. Herein, we identify HSF5 as a male germ cell-specific heat shock transcription factor (HSF) for meiotic prophase progression. Genetic analyzes and single-cell RNA-sequencing demonstrate that HSF5 is essential for progression beyond the pachytene stage under non-stress conditions rather than heat stress. Chromatin binding analysis in vivo and DNA-binding assays in vitro suggest that HSF5 binds to promoters in a subset of genes associated with chromatin organization. HSF5 recognizes a DNA motif different from typical heat shock elements recognized by other canonical HSFs. This study suggests that HSF5 is an atypical HSF that is required for the gene expression program for pachytene transition during meiotic prophase in males.


Subject(s)
Heat Shock Transcription Factors , Meiotic Prophase I , Spermatogenesis , Mice , Male , Heat Shock Transcription Factors/metabolism , Mice, Knockout , Mice, Inbred C57BL , Testis/metabolism , Heat-Shock Response , Female
2.
Nat Commun ; 14(1): 6443, 2023 10 25.
Article in English | MEDLINE | ID: mdl-37880249

ABSTRACT

Meiosis is differently regulated in males and females. In females, germ cells initiate meiosis within a limited time period in the fetal ovary and undergo a prolonged meiotic arrest until puberty. However, how meiosis initiation is coordinated with the cell cycle to coincide with S phase remains elusive. Here, we demonstrate that STRA8 binds to RB via the LXCXE motif. Mutation of the RB-binding site of STRA8 in female mice delays meiotic entry, which consequently delays progression of meiotic prophase and leads to precocious depletion of the oocyte pool. Single-cell RNA-sequencing analysis reveals that the STRA8-RB interaction is required for S phase entry and meiotic gene activation, ensuring precise timing of meiosis initiation in oocytes. Strikingly, the results suggest STRA8 could sequester RB from E2F during pre-meiotic G1/S transition. This study highlights the gene regulatory mechanisms underlying the female-specific mode of meiotic initiation in mice.


Subject(s)
Adaptor Proteins, Signal Transducing , Meiosis , Animals , Female , Male , Mice , Adaptor Proteins, Signal Transducing/metabolism , Gene Expression Regulation , Germ Cells/metabolism , Sexual Maturation , Retinoblastoma Protein
3.
Nat Metab ; 4(2): 180-189, 2022 02.
Article in English | MEDLINE | ID: mdl-35228746

ABSTRACT

Adult skeletal muscle is a highly plastic tissue that readily reduces or gains its mass in response to mechanical and metabolic stimulation; however, the upstream mechanisms that control muscle mass remain unclear. Notch signalling is highly conserved, and regulates many cellular events, including proliferation and differentiation of various types of tissue stem cell via cell-cell contact. Here we reveal that multinucleated myofibres express Notch2, which plays a crucial role in disuse- or diabetes-induced muscle atrophy. Mechanistically, in both atrophic conditions, the microvascular endothelium upregulates and releases the Notch ligand, Dll4, which then activates muscular Notch2 without direct cell-cell contact. Inhibition of the Dll4-Notch2 axis substantively prevents these muscle atrophy and promotes mechanical overloading-induced muscle hypertrophy in mice. Our results illuminate a tissue-specific function of the endothelium in controlling tissue plasticity and highlight the endothelial Dll4-muscular Notch2 axis as a central upstream mechanism that regulates catabolic signals from mechanical and metabolic stimulation, providing a therapeutic target for muscle-wasting diseases.


Subject(s)
Adaptor Proteins, Signal Transducing , Calcium-Binding Proteins , Muscular Atrophy , Animals , Endothelium , Mice , Muscle, Skeletal , Receptor, Notch2
5.
Genes Dev ; 29(16): 1763-75, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26302791

ABSTRACT

Sensory neurons with common functions are often nonrandomly arranged and form dendritic territories in stereotypic spatial patterns throughout the nervous system, yet molecular mechanisms of how neurons specify dendritic territories remain largely unknown. In Drosophila larvae, dendrites of class IV sensory (C4da) neurons completely but nonredundantly cover the whole epidermis, and the boundaries of these tiled dendritic fields are specified through repulsive interactions between homotypic dendrites. Here we report that, unlike the larval C4da neurons, adult C4da neurons rely on both dendritic repulsive interactions and external positional cues to delimit the boundaries of their dendritic fields. We identify Wnt5 derived from sternites, the ventral-most part of the adult abdominal epidermis, as the critical determinant for the ventral boundaries. Further genetic data indicate that Wnt5 promotes dendrite termination on the periphery of sternites through the Ryk receptor family kinase Derailed (Drl) and the Rho GTPase guanine nucleotide exchange factor Trio in C4da neurons. Our findings thus uncover the dendritic contact-independent mechanism that is required for dendritic boundary specification and suggest that combinatory actions of the dendritic contact-dependent and -independent mechanisms may ensure appropriate dendritic territories of a given neuron.


Subject(s)
Dendrites , Drosophila Proteins/metabolism , Drosophila melanogaster/cytology , Drosophila melanogaster/metabolism , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Sensory Receptor Cells , Signal Transduction , Wnt Proteins/metabolism , Animals , Dendrites/genetics , Dendrites/metabolism , Drosophila melanogaster/enzymology , Drosophila melanogaster/genetics , Epidermal Cells , Epidermis/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Sensory Receptor Cells/cytology , Sensory Receptor Cells/metabolism
6.
Nat Commun ; 6: 6515, 2015 Mar 12.
Article in English | MEDLINE | ID: mdl-25761586

ABSTRACT

The refinement of neural circuits involves dendrite pruning, a process that removes inappropriate projections that are formed during development. In Drosophila sensory neurons, compartmentalized calcium (Ca(2+)) transients in dendrites act as spatiotemporal cues to trigger pruning, yet how neurons define the dendrites with Ca(2+) transients remains elusive. Here we report that local elevation of endocytic activity contributes to defining dendrites that generate Ca(2+) transients, triggering pruning. In vivo imaging of single dendrites reveals an increase of endocytosis in proximal dendrites that spatially and temporally correlates with dendrite thinning, an early step in pruning tightly coupled with compartmentalized Ca(2+) transients. Two GTPases, Rab5 and dynamin, are required for both the increased endocytic activity and compartmentalized Ca(2+) transients. Further genetic analyses suggest that local endocytosis in proximal dendrites functions cooperatively with global endocytosis-mediated protein degradation pathways to promote dendrite pruning.


Subject(s)
Dendrites/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Dynamins/genetics , Endocytosis/genetics , Neuronal Plasticity/genetics , rab5 GTP-Binding Proteins/genetics , Animals , Animals, Genetically Modified , Calcium/metabolism , Calcium Signaling , Cell Compartmentation , Dendrites/ultrastructure , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Dynamins/metabolism , Endosomes/metabolism , Gene Expression Regulation, Developmental , Metamorphosis, Biological/genetics , Molecular Imaging , Proteolysis , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/ultrastructure , rab5 GTP-Binding Proteins/metabolism
7.
Science ; 340(6139): 1475-8, 2013 Jun 21.
Article in English | MEDLINE | ID: mdl-23722427

ABSTRACT

Dendrite pruning is critical for sculpting the final connectivity of neural circuits as it removes inappropriate projections, yet how neurons can selectively eliminate unnecessary dendritic branches remains elusive. Here, we show that calcium transients that are compartmentalized in specific dendritic branches act as temporal and spatial cues to trigger pruning in Drosophila sensory neurons. Calcium transients occurred in local dendrites at ~3 hours before branch elimination. In dendritic branches, intrinsic excitability increased locally to activate calcium influx via the voltage-gated calcium channels (VGCCs), and blockade of the VGCC activities impaired pruning. Further genetic analyses suggest that the calcium-activated protease calpain functions downstream of the calcium transients. Our findings reveal the importance of the compartmentalized subdendritic calcium signaling in spatiotemporally selective elimination of dendritic branches.


Subject(s)
Calcium/metabolism , Dendrites/physiology , Sensory Receptor Cells/physiology , Animals , Calcium Channels/metabolism , Calcium Signaling , Calpain/genetics , Calpain/metabolism , Dendrites/ultrastructure , Drosophila Proteins/metabolism , Drosophila melanogaster , Female , Male , Metamorphosis, Biological
8.
Nat Commun ; 4: 1825, 2013.
Article in English | MEDLINE | ID: mdl-23652013

ABSTRACT

Female Drosophila with the spinster mutation repel courting males and rarely mate. Here we show that the non-copulating phenotype can be recapitulated by the elimination of spinster functions from either spin-A or spin-D neuronal clusters, in the otherwise wild-type (spinster heterozygous) female brain. Spin-D corresponds to the olfactory projection neurons with dendrites in the antennal lobe VA1v glomerulus that is fruitless-positive, sexually dimorphic and responsive to fly odour. Spin-A is a novel local neuron cluster in the suboesophageal ganglion, which is known to process contact chemical pheromone information and copulation-related signals. A slight reduction in spinster expression to a level with a minimal effect is sufficient to shut off female sexual receptivity if the dominant-negative mechanistic target of rapamycin is simultaneously expressed, although the latter manipulation alone has only a marginal effect. We propose that spin-mediated mechanistic target of rapamycin signal transduction in these neurons is essential for females to accept the courting male.


Subject(s)
Drosophila melanogaster/cytology , Drosophila melanogaster/physiology , Interneurons/cytology , Sexual Behavior, Animal/physiology , Animals , Copulation/drug effects , Drosophila Proteins/metabolism , Drosophila melanogaster/drug effects , Female , Heterozygote , Homozygote , Interneurons/drug effects , Interneurons/metabolism , Male , Membrane Proteins/metabolism , Neuroglia/cytology , Neuroglia/drug effects , Neuroglia/metabolism , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Olfactory Pathways/drug effects , Olfactory Pathways/metabolism , RNA Interference/drug effects , Receptors, Odorant/metabolism , Sexual Behavior, Animal/drug effects , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism
9.
Biochem Res Int ; 2012: 789083, 2012.
Article in English | MEDLINE | ID: mdl-22567285

ABSTRACT

The brain changes in response to experience and altered environment. To do that, the nervous system often remodels the structures of neuronal circuits. This structural plasticity of the neuronal circuits appears to be controlled not only by intrinsic factors, but also by extrinsic mechanisms including modification of the extracellular matrix. Recent studies employing a range of animal models implicate that matrix metalloproteinases regulate multiple aspects of the neuronal development and remodeling in the brain. This paper aims to summarize recent advances of our knowledge on the neuronal functions of matrix metalloproteinases and discuss how they might relate in neuronal disease.

10.
Proc Natl Acad Sci U S A ; 108(48): 19389-94, 2011 Nov 29.
Article in English | MEDLINE | ID: mdl-22084112

ABSTRACT

The axonal projection pattern of sensory neurons typically is regulated by environmental signals, but how different sensory afferents can establish distinct projections in the same environment remains largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons project subtype-specific axonal branches in the ventral nerve cord, and we show that the Tripartite motif protein, Anomalies in sensory axon patterning (Asap) is a critical determinant of the axonal projection patterns of different C4da neurons. Asap is highly expressed in C4da neurons with both ipsilateral and contralateral axonal projections, but the Asap level is low in neurons that have only ipsilateral projections. Mutations in asap cause a specific loss of contralateral projections, whereas overexpression of Asap induces ectopic contralateral projections in C4da neurons. We also show by biochemical and genetic analysis that Asap regulates Netrin signaling, at least in part by linking the Netrin receptor Frazzled to the downstream effector Pico. In the absence of Asap, the sensory afferent connectivity within the ventral nerve cord is disrupted, resulting in specific larval behavioral deficits. These results indicate that different levels of Asap determine distinct patterns of axonal projections of C4da neurons by modulating Netrin signaling and that the Asap-mediated axonal projection is critical for assembly of a functional sensory circuit.


Subject(s)
Axons/metabolism , Drosophila Proteins/metabolism , Drosophila/physiology , Nerve Tissue Proteins/metabolism , Neurogenesis/physiology , Sensory Receptor Cells/physiology , Signal Transduction/physiology , Animals , Axons/physiology , Drosophila Proteins/genetics , Immunoprecipitation , Nerve Tissue Proteins/genetics , Netrin Receptors , Receptors, Cell Surface/metabolism , Sensory Receptor Cells/cytology , Signal Transduction/genetics , Two-Hybrid System Techniques
11.
Dev Cell ; 18(4): 621-32, 2010 Apr 20.
Article in English | MEDLINE | ID: mdl-20412776

ABSTRACT

In response to changes in the environment, dendrites from certain neurons change their shape, yet the mechanism remains largely unknown. Here we show that dendritic arbors of adult Drosophila sensory neurons are rapidly reshaped from a radial shape to a lattice-like shape within 24 hr after eclosion. This radial-to-lattice reshaping arises from rearrangement of the existing radial branches into the lattice-like pattern, rather than extensive dendrite pruning followed by regrowth of the lattice-shaped arbors over the period. We also find that the dendrite reshaping is completely blocked in mutants for the matrix metalloproteinase (Mmp) 2. Further genetic analysis indicates that Mmp2 promotes the dendrite reshaping through local degradation of the basement membrane upon which dendrites of the sensory neurons innervate. These findings suggest that regulated proteolytic alteration of the extracellular matrix microenvironment might be a fundamental mechanism to drive a large-scale change of dendritic structures during reorganization of neuronal circuits.


Subject(s)
Basement Membrane/enzymology , Drosophila melanogaster/metabolism , Gene Expression Regulation, Enzymologic , Matrix Metalloproteinases/metabolism , Neurons/metabolism , Animals , Dendrites/metabolism , Epithelial Cells/enzymology , Extracellular Matrix/metabolism , Female , Male , Models, Biological , Models, Genetic , Muscles/enzymology , Time Factors
12.
EMBO J ; 28(24): 3879-92, 2009 Dec 16.
Article in English | MEDLINE | ID: mdl-19875983

ABSTRACT

To cover the receptive field completely and non-redundantly, neurons of certain functional groups arrange tiling of their dendrites. In Drosophila class IV dendrite arborization (da) neurons, the NDR family kinase Tricornered (Trc) is required for homotypic repulsion of dendrites that facilitates dendritic tiling. We here report that Sin1, Rictor, and target of rapamycin (TOR), components of the TOR complex 2 (TORC2), are required for dendritic tiling of class IV da neurons. Similar to trc mutants, dendrites of sin1 and rictor mutants show inappropriate overlap of the dendritic fields. TORC2 components physically and genetically interact with Trc, consistent with a shared role in regulating dendritic tiling. Moreover, TORC2 is essential for Trc phosphorylation on a residue that is critical for Trc activity in vivo and in vitro. Remarkably, neuronal expression of a dominant active form of Trc rescues the tiling defects in sin1 and rictor mutants. These findings suggest that TORC2 likely acts together with the Trc signalling pathway to regulate the dendritic tiling of class IV da neurons, and thus uncover the first neuronal function of TORC2 in vivo.


Subject(s)
Dendrites/metabolism , Drosophila Proteins/metabolism , Drosophila Proteins/physiology , Drosophila melanogaster/metabolism , Neurons/metabolism , Phosphatidylinositol 3-Kinases/physiology , Protein Serine-Threonine Kinases/metabolism , Animals , Carrier Proteins/metabolism , Crosses, Genetic , HeLa Cells , Humans , Mutation , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation , Protein Kinases , Rapamycin-Insensitive Companion of mTOR Protein , Sensory Receptor Cells/metabolism , Signal Transduction , TOR Serine-Threonine Kinases
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