Biology subjects

Rice, M.

Publications and source records attributed to Rice, M..

9 recordsLinked to original sources

bioRxiv2026

MOTS-c Coordinates Inter-Organellar Proteostasis for Adaptation to Chronic Metabolic Stress

Mitochondrial communication coordinates adaptive responses across organelles to sustain cellular homeostasis, a network that declines with age and contributes to loss of proteostasis. Here, we identify MOTS-c, an exercise-induced mitochondrial-derived peptide (MDP) encoded within the 12S rRNA locus, as an inter-organellar arm of the mitochondrial stress response (MSR) that links mitochondrial signaling to endoplasmic reticulum (ER) proteostasis and enables adaptation to chronic stress. Using progressive stress media (PSM), a model of gradual and multifactorial metabolic stress, we show that MOTS-c enables adaptation through a biphasic program: acutely, a reversible, ATF4-independent suppression of protein synthesis; and chronically, an ATF6-biased ER unfolded protein response (UPRER) with tempered ATF4 engagement and coordinated metabolic remodeling. Whereas mitochondrial unfolded protein response (UPRmt) pathways have been extensively characterized in acute, genetic, and sustained models of mitochondrial perturbation, this work reveals how mitochondrial communication actively engages ER proteostasis during progressive and persistent metabolic stress. By expanding proteostatic capacity while tempering terminal stress signaling, MOTS-c enables cells to withstand chronic stress. Together, these findings define a MOTS-c-dependent arm of the MSR that integrates mitochondrial communication with ER proteostasis to promote chronic metabolic stress adaptation.

Cell Biology↗

bioRxiv2026

Age dependent impairment of home cage behavior and reactivity in Cntnap2 knock out mouse model

Contactin-associated protein-like 2 (CNTNAP2) is a transmembrane protein that mediates neuron-glia interactions and regulates dendritic spine growth and neuronal migration. Mutations in the CNTNAP2 gene are linked to autism and epilepsy. Younger Cntnap2 KO mice mimic autism phenotypes, while older mice are a model for epilepsy. Thus, comparing behavioral phenotypes across different ages is needed to better understand the age dependent development of disordered brain networks in Cntnap2 mutants. Male and female Cntnap2 KO and WT controls were tested across different age groups (4, 5, 7, 9, and [~]11 months) using digging, stimulus (reactivity), and nesting assays. Older Cntnap2 KO mice (7, 9, and [~]11 months) showed a significant increase in home cage reactivity (stimulus) assay compared to younger mice at 4 and 5 months of age. Similar trends were observed in male and female Cntnap2 KO mice. No significant differences were observed in WT controls. A significant difference in digging assay was observed in KO female mice between younger (4 month) and older mice post nest removal. An age-dependent significant reduction in nesting behavior was observed in female KO mice; however, no difference was observed in the WT controls. Immunohistochemical analysis showed age dependent change interneuron and microglial network in Cntnap2 KO mice. Our findings suggest disruption in home cage behavior and reactivity in older pre-epileptic Cntnap2 KO mice indicating an age-dependent network alteration and behavior deficits. Significance StatementThis study investigates the age-dependent behavioral changes in Cntnap2 KO mice due to underlying changes in the neuronal network. It has been shown that younger Cntnap2 KO mice display autistic behaviors and that older Cntnap2 KO mice have epilepsy, but it is unknown how behavior is affected during the intervening period of epileptogenesis. We find that female Cntnap2 KO mice at 11 months of age have increased reactivity and decreased motor activity compared to younger age groups, whereas WT mice show no relationship between age and behavior. Overall, the loss of Cntnap2 alters behavior in an age-dependent and sex-specific manner, indicating progressive dysregulation of the neuronal network.

neuroscience↗

bioRxiv2025

Multiplexing Light-Inducible Recombinases to Control Cell Fate, Boolean Logic, and Cell Patterning in Mammalian Cells

Light-inducible regulatory proteins are powerful tools to interrogate fundamental mechanisms driving cellular behavior. In particular, genetically encoded photosensory domains fused to split proteins can tightly modulate protein activity and gene expression. While light-inducible split protein systems have performed well individually, few multichromatic and orthogonal gene regulation systems exist in mammalian cells. The design space for multichromatic circuits is limited by the small number of orthogonally addressable optogenetic switches and the types of effectors that can be actuated by them. We developed a library of red light-inducible recombinases and directed patterned myogenesis in a mesenchymal fibroblast-like cell line. To address the limited number of light-inducible domains (LIDs) responding to unique excitation spectra, we multiplexed light-inducible recombinases with our Boolean Logic and Arithmetic through DNA Excision (BLADE) platform. Multiplexed optogenetic tools will be transformative for understanding the role of multiple interacting genes and their spatial context in endogenous signaling networks.

molecular biology↗

bioRxiv2024

CD2AP is Co-Expressed with Tropomyosin-Related Kinase A and Ras-Related Protein Rab-5A in Cholinergic Neurons of the Murine Basal Forebrain

Genome-wide association studies (GWAS) with multiple human populations have uncovered single nucleotide variants of the CD2AP gene locus that are associated with Alzheimers Disease (AD) risk. However, the role of CD2AP in AD pathogenesis remains unknown. In adult PNS neurons, previous work demonstrated that CD2AP functions as a docking-scaffold/adaptor protein coordinator of nerve growth factor (NGF) trophic signaling and RAB5-mediated endocytosis. In the adult CNS, whereas CD2AP is robustly expressed in non-neuronal cells and neurovasculature, neuronal expression is restricted and poorly characterized. In this study using publicly available single cell/nucleus RNA sequencing, we observed that CD2AP mRNA is enriched in a population of TrkA-expressing cholinergic neurons of the adult mouse basal forebrain. Immunohistology using brain tissue from adult choline acetyltransferase (ChAT) GFP reporter mice, confirmed enrichment of CD2AP protein in cholinergic projections, and in neuron soma in the diagonal band of Broca where it co-localized with RAB5. Together with previous studies from NGF-responsive PNS primary sensory neurons, these observations indicate that CD2AP may play a role in retrograde trophic signaling in NGF- responsive CNS cholinergic neurons. In addition, we observed that CD2AP expression in these soma was increased in aged mice (18-month-old), concomitant with a reduction of co-localization with RAB5, suggesting a potential role for CD2AP in aging-associated changes in retrograde trophic signaling in these neurons. Basal forebrain cholinergic neurons project to the hippocampus and cortex, are required for learning and memory, are critical for brain health during aging, and disruption of RAB5 mediated endocytosis in these neurons is central to the pathogenesis of Alzheimers disease (AD). Future studies are therefore warranted to determine if CD2AP risk variants impact endocytosis and trophic signaling in cholinergic neurons in healthy aging and/or AD.

neuroscience↗

bioRxiv2024

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

Misprocessing of Amyloid Precursor Protein (APP) is one of the major causes of Alzheimers disease. APP is a transmembrane protein comprising a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talins are synaptic scaffold proteins that connect the cytoskeletal machinery to the plasma membrane via binding to one of two highly conserved NPxY motifs in the cytoplasmic tail of integrin transmembrane receptors. Here we report the crystal structure of an APP/talin1 complex identifying a new way to couple the cytoskeletal machinery to synaptic sites via APP. Proximity Ligation Assay (PLA) confirmed the close proximity of talin1 and APP in primary neurons, and we show that talin1 depletion has a dramatic effect on APP processing in cells. Structural modelling indicates that APP has the capacity to form an extracellular meshwork that mechanically couples the cytoskeletal meshworks of both the pre-, and post-synaptic compartments. In this context, we propose APP processing as a mechanical signalling pathway with similarities to Notch signalling, whereby the cleavage sites in APP represent mechanical sensors, with varying accessibility to cleavage by secretases. During synaptogenesis in healthy neurons, the APP/talin linkage would provide an exquisite mechanical coupling between synapses, with tightly controlled APP processing providing instructions to maintain this synchrony. Furthermore, APP directly coupling to the binary switches in talin indicates a role for APP in mechanical memory storage as postulated by the MeshCODE theory. The implication that APP is a regulator of mechanical signalling leads to a new hypothesis for Alzheimers disease, where mis-regulation of APP dynamics results in loss of mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of the toxic plaque-forming A{beta}42 peptide. Much needs to be done to experimentally validate this idea, but we present here a novel theory of Alzheimers Disease with a role for APP in the mechanically coded binary information storage in the synapse, which identifies a potential novel therapeutic strategy for treating Alzheimers Disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/583202v4_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@ba0768org.highwire.dtl.DTLVardef@13c4672org.highwire.dtl.DTLVardef@352178org.highwire.dtl.DTLVardef@288bf6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Graphical Abstract Legend: Amyloid Precursor Protein (APP) forms an extracellular meshwork that provides a coupling between the mechanical signalling machinery of the pre- and post-synaptic neurons.A) APP binds to talin indicating that APP will experience mechanical forces which leads us to propose that APP processing is a Notch-like signalling pathway that maintains mechanical homeostasis at the synapse. B) The crystal structure of APP bound to talin F2F3. C) APP is part of the adhesion complex that attaches talin to the membrane. D) The loss of adhesion integrity in the synapse, or other factors that lead to misprocessing of APP will perturb this coupling and contribute to Alzheimers Disease. See also Movie 1. C_FIG

neuroscience↗

bioRxiv2023

Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-DHF, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6, and a promising therapeutic target.

neuroscience↗

bioRxiv2023

Loss of IRF5 increases ribosome biogenesis leading to alterations in mammary gland architecture and metastasis

Despite the progress made in identifying cellular factors and mechanisms that predict progression and metastasis, breast cancer remains the second leading cause of death for women in the US. Using The Cancer Genome Atlas and mouse models of spontaneous and invasive mammary tumorigenesis, we identified that loss of function of interferon regulatory factor 5 (IRF5) is a predictor of metastasis and survival. Histologic analysis of Irf5-/- mammary glands revealed expansion of luminal and myoepithelial cells, loss of organized glandular structure, and altered terminal end budding and migration. RNA-seq and ChIP-seq analyses of primary mammary epithelial cells from Irf5+/+ and Irf5-/-littermate mice revealed IRF5-mediated transcriptional regulation of proteins involved in ribosomal biogenesis. Using an invasive model of breast cancer lacking Irf5, we demonstrate that IRF5 re-expression inhibits tumor growth and metastasis via increased trafficking of tumor infiltrating lymphocytes and altered tumor cell protein synthesis. These findings uncover a new function for IRF5 in the regulation of mammary tumorigenesis and metastasis. HighlightsLoss of IRF5 is a predictor of metastasis and survival in breast cancer. IRF5 contributes to the regulation of ribosome biogenesis in mammary epithelial cells. Loss of IRF5 function in mammary epithelial cells leads to increased protein translation.

cancer biology↗

bioRxiv2023

Knockdown of Atg1 or Atg18 in adult adipocytes impairs lipophagy and reduces lifespan of fruit flies (Drosophila melanogaster)

Autophagy, a lysosome-based eukaryotic cellular degradation system, has previously been implicated in lifespan regulation in different animal models. In this report, we show that expression of the RNAi transgenes targeting the transcripts of the key autophagy genes such as Atg1 or Atg18 in adult fly muscle or glia does not affect the overall levels of autophagosomes in those tissues and does not change the lifespan of the tested flies, but lifespan reduction phenotype has become apparent when Atg1 RNAi or Atg18 RNAi is expressed in a non-tissue-specific manner through a Tub-Gal4 in adult flies or after lipophagy is eradicated through the knockdown of Atg1 or Atg18 in adult fly adipocytes. Lifespan reduction was also observed when Atg1 or Atg18 was knocked down in adult fly enteroblasts and middle gut stem cells. Over-expression of wildtype Atg1 in adult fly muscle or adipocytes reduces lifespan. High levels of ubiquitinated protein aggregates could be the culprit of the reduced lifespan of Atg1 over-expression flies. Our research data presented here have highlighted the important functions of the key autophagy genes in adult fly adipocytes, enteroblasts, and midgut stem cells for lifespan regulation and their undetermined functions in adult fly muscle and glia. SummaryIn this research, we have demonstrated that the key autophagy genes play important roles in fly lifespan regulation through adult adipose tissues, enteroblasts, and middle gut stem cells.

genetics↗

bioRxiv2018

Accounting for location uncertainty in azimuthal telemetry data improves ecological inference

Characterizing animal space use is critical to understand ecological relationships. Despite many decades of using radio-telemetry to track animals and make spatial inference, there are few statistical options to handle these unique data and no synthetic framework for modeling animal location uncertainty and accounting for it in ecological models. We describe a novel azimuthal telemetry model (ATM) to account for azimuthal uncertainty with covariates and propagate location uncertainty into ecological models. We evaluate the ATM with commonly used estimators in several study design scenarios using simulation. We also provide illustra-tive empirical examples, demonstrating the impact of ignoring location uncertainty within home range and resource selection analyses. We found the ATM to have good performance and the only model that has appropriate measures of coverage. Ignoring animal location un-certainty when estimating resource selection or home ranges can have pernicious effects on ecological inference. We demonstrate that home range estimates can be overly confident and conservative when ignoring location uncertainty and resource selection coefficients can lead to incorrect inference and over confidence in the magnitude of selection. Our findings and model development have important implications for interpreting historical analyses using this type of data and the future design of radio-telemetry studies.

ecology↗