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Nature Genetics Oct 2023Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria...
Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy. However, the causative mechanisms of paternal mtDNA elimination have not been defined. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.
Topics: Humans; Male; DNA, Mitochondrial; Maternal Inheritance; Semen; Mitochondria; Spermatozoa; Mitochondrial Proteins
PubMed: 37723262
DOI: 10.1038/s41588-023-01505-9 -
Nature Dec 2023The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a...
The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.
Topics: Animals; Mice; Gene Expression Profiling; Hypothalamus; Neurons; Neuropeptides; Spinal Cord; Brain; Neural Pathways; Neurotransmitter Agents; Mesencephalon; Reticular Formation; Electrophysiology; Cerebellum; Cerebral Cortex
PubMed: 38092914
DOI: 10.1038/s41586-023-06817-8 -
Molecular Cancer Jul 2023Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and...
Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N-methylguanosine (mG) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of mG tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed mG tRNA methylation in cancer cell translation control and tumour biology.
Topics: Male; Humans; Carcinogenesis; Cell Transformation, Neoplastic; Prostatic Neoplasms; Transcription, Genetic; RNA Processing, Post-Transcriptional; Methyltransferases
PubMed: 37516825
DOI: 10.1186/s12943-023-01809-8 -
Nature Communications Oct 2023Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid...
Previous studies have speculated that brain activity directly controls immune responses in lymphoid organs. However, the upstream brain regions that control lymphoid organs and how they interface with lymphoid organs to produce stress-induced anxiety-like behavior remain elusive. Using stressed human participants and rat models, we show that CCL5 levels are increased in stressed individuals compared to controls. Stress-inducible CCL5 is mainly produced from cervical lymph nodes (CLN). Retrograde tracing from CLN identifies glutamatergic neurons in the red nucleus (RN), the activities of which are tightly correlated with CCL5 levels and anxiety-like behavior in male rats. Ablation or chemogenetic inhibition of RN glutamatergic neurons increases anxiety levels and CCL5 expression in the serum and CLNs, whereas pharmacogenetic activation of these neurons reduces anxiety levels and CCL5 synthesis after restraint stress exposure. Chemogenetic inhibition of the projection from primary motor cortex to RN elicits anxiety-like behavior and CCL5 synthesis. This brain-lymph node axis provides insights into lymph node tissue as a stress-responsive endocrine organ.
Topics: Rats; Humans; Male; Animals; Red Nucleus; Stress, Psychological; Anxiety; Lymph Nodes; Brain; Chemokine CCL5
PubMed: 37903803
DOI: 10.1038/s41467-023-42814-1 -
Scientific Reports Jul 2023Cleidocranial dysplasia (CCD) is a genetic disorder caused by mutations in the RUNX2 gene, affecting bone and teeth development. Previous studies focused on mutations in...
Cleidocranial dysplasia (CCD) is a genetic disorder caused by mutations in the RUNX2 gene, affecting bone and teeth development. Previous studies focused on mutations in the RUNX2 RHD domain, with limited investigation of mutations in the C-terminal domain. This study aimed to investigate the functional consequences of C-terminal mutations in RUNX2. Eight mutations were analyzed, and their effects on transactivation activity, protein expression, subcellular localization, and osteogenic potential were studied. Truncating mutations in the PST region and a missense mutation in the NMTS region resulted in increased transactivation activity, while missense mutations in the PST showed activity comparable to the control. Truncating mutations produced truncated proteins, while missense mutations produced normal-sized proteins. Mutant proteins were mislocalized, with six mutant proteins detected in both the nucleus and cytoplasm. CCD patient bone cells exhibited mislocalization of RUNX2, similar to the generated mutant. Mislocalization of RUNX2 and reduced expression of downstream genes were observed in MSCs from a CCD patient with the p.Ser247Valfs*3 mutation, leading to compromised osteogenic potential. This study provides insight into the functional consequences of C-terminal mutations in RUNX2, including reduced expression, mislocalization, and aberrant transactivation of downstream genes, contributing to the compromised osteogenic potential observed in CCD.
Topics: Humans; Core Binding Factor Alpha 1 Subunit; Mutation; Mutation, Missense; Cleidocranial Dysplasia
PubMed: 37500953
DOI: 10.1038/s41598-023-39293-1