Biology subjects

Jing, J.

Publications and source records attributed to Jing, J..

29 records · Page 2Linked to original sources

bioRxiv2022

Dual control of meiotic crossover patterning

Most meiotic crossovers (COs), called class I crossovers, are produced by a conserved pathway catalyzed by the ZMM proteins; COs are limited in number, typically to 1-3 per chromosome, and are prevented from occurring close to one other by crossover interference1-3. In many species, CO number is subject to dimorphism between males and females, and a lower CO number is associated with shorter chromosome axes and stronger interference4. How the patterning of COs is imposed, however, remains poorly understood. Here, we show that overexpression of the ZMM protein HEI10 increases COs and reduces crossover interference but maintains sexual dimorphism; shorter axes length in female meiosis is still associated with fewer COs and stronger interference than in male meiocytes. Disrupting the synaptonemal complex (SC) by mutating ZYP1 also leads to an increase in class I COs but, in contrast, abolishes interference and disrupts the link between chromosome axis length and COs, with female and male meiocytes having the same CO frequency despite different axis lengths. Combining HEI10 overexpression and zyp1 mutation leads to a massive increase in class I COs and absence of interference, while axes lengths are still unaffected. These observations support, and can be effectively predicted by, a recently proposed coarsening model5,6 in which HEI10 diffusion is funneled by the central element of the SC before coarsening into large, well-spaced CO-promoting droplets. Given the conservation of the components, this model may account for CO patterning in many eukaryotes.

genetics↗

bioRxiv2022

Cellular and Circuit Organization of the Locus Coeruleus of Adult Mice

The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.

neuroscience↗

bioRxiv2022

Functional characterization of a neuropeptide receptor exogenously expressed in Aplysia neurons

Neuropeptides act mostly on a class of G-protein coupled receptors, and play a fundamental role in the functions of neural circuits underlying behaviors. However, the functions of neuropeptide receptors are poorly understood. Here, we used the mollusc model system Aplysia and microinjected the exogenous neuropeptide receptor apATRPR (Aplysia Allatotropin-related peptide receptor) with an expression vector (pNEX3) into Aplysia neurons that did not express the receptor. Physiological experiments demonstrated that apATRPR could mediate the excitability increase activated by its ligand, apATRP (Aplysia Allatotropin-related peptide), in the Aplysia neurons that now express the receptor. This study provides the first definitive evidence for a physiological function of a neuropeptide receptor in molluscan animals.

neuroscience↗

bioRxiv2021

Kdm6b confers Tfdp1 with the competence to activate p53 signalling in regulating palatogenesis

Epigenetic regulation plays extensive roles in diseases and development. Disruption of epigenetic regulation not only increases the risk of cancer, but can also cause various developmental defects. However, it is still unclear how epigenetic regulators coordinate with tissue-specific regulatory factors during morphogenesis of specific organs. Using palatogenesis as a model, we reveal the functional significance of Kdm6b, a H3K27me3 demethylase, in regulating embryonic development. Our study shows that Kdm6b plays an essential role in neural crest development, and loss of Kdm6b disturbs p53 pathway-mediated activity, leading to complete cleft palate along with cell proliferation and differentiation defects. Furthermore, activity of H3K27me3 on the promoter of p53 is precisely controlled by Kdm6b, and Ezh2 in regulating p53 expression in cranial neural crest cells. More importantly, Kdm6b renders chromatin accessible to the transcription factor Tfdp1, which binds to the promoter of p53 along with Kdm6b to specifically activate p53 expression during palatogenesis. Collectively our results highlight the important role of the epigenetic regulator Kdm6b and how it cooperates with Tfdp1 to achieve its functional specificity in regulating p53 expression, and further provide mechanistic insights into the epigenetic regulatory network during organogenesis.

developmental biology↗

bioRxiv2020

Removal of KCNQ2 from Parvalbumin-expressing Interneurons Improves Anti-Seizure Efficacy of Retigabine

Anti-seizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2fl/fl), RTG (10 mg/kg, i.p.) significantly delayed the onset of either picrotoxin (PTX, 10 mg/kg, i.p)- or kainic acid (KA, 30mg/kg, i.p.)-induced convulsive seizures compared to vehicle, while RTG was not effective in wild-type littermates (WT). Immunostaining for KCNQ2 and KCNQ3 revealed that both subunits were enriched at axon initial segments (AISs) of hippocampal CA1 PV-INs, and their specific expression was selectively abolished in cKO mice. Accordingly, the M-currents recorded from CA1 PV-INs and their sensitivity to RTG were significantly reduced in cKO mice. While the ability of RTG to suppress CA1 excitatory neurons in hippocampal slices was unchanged in cKO mice, its suppressive effect on the spike activity of CA1 PV-INs was significantly reduced compared with WT mice. In addition, the RTG-induced suppression on intrinsic membrane excitability of PV-INs in WT mice was significantly reduced in cKO mice. These findings suggest that preventing RTG from suppressing PV-INs improves its anticonvulsant effect. Significance StatementOne out of three patients with epilepsy remain resistant to anti-seizure drugs (ASD). Therefore, strategies that can enhance the efficacy of current ASDs or aid in the development of novel ASDs are in high demand. Here we show that by sparing a subset of inhibitory neurons, the ASD retigabine becomes more efficacious. These findings indicate that developing the ASDs that have relatively greater effects on excitatory over inhibitory neurons may be an effective strategy to improve the efficacy of ASDs.

neuroscience↗

bioRxiv2020

Epigenetic Interaction between UTX and DNMT1 Regulates Diet-Induced Myogenic Remodeling in Brown Fat

Brown adipocytes share the same developmental origin with skeletal muscle. Here we find that a brown adipocyte-to-myocyte remodeling also exists in mature brown adipocytes, and is induced by prolonged high fat diet (HFD) feeding, leading to brown fat dysfunction. This process is regulated by the interaction of epigenetic pathways involving histone and DNA methylation. In mature brown adipocytes, the histone demethylase UTX maintains persistent demethylation of the repressive mark H3K27me3 at Prdm16 promoter, leading to high Prdm16 expression. PRDM16 then recruits DNA methyltransferase DNMT1 to Myod1 promoter, causing Myod1 promoter hypermethylation and suppressing its expression. The interaction between PRDM16 and DNMT1 coordinately serves to maintain brown adipocyte identity while repressing myogenic remodeling in mature brown adipocytes, thus promoting their active brown adipocyte thermogenic function. Suppressing this interaction by HFD feeding induces brown adipocyte-to-myocyte remodeling, which limits brown adipocyte thermogenic capacity and compromises diet-induced thermogenesis, leading to the development of obesity.

physiology↗

bioRxiv2020

ZmMTOPVIB is essential for double-strand break formation and bipolar spindle assembly in maize meiosis

The programmed formation of DNA double-strand breaks (DSBs) during early meiosis is catalyzed by SPO11, a conserved ortholog to the A subunit of an archaeal topoisomerase VI (TopoVI) which functions as a hetero-tetramer comprising two A and two B subunits. An essential role of the meiotic TopoVI B subunit (TopVIB) in DSB formation has been reported in mouse, Arabidopsis and rice. Very recently, rice MTopVIB was revealed to have an unexpected role in meiotic bipolar spindle assembly, highlighting multiple functions of MTopVIB during rice meiosis. In this work, the meiotic TopVIB in maize (ZmMTOPVIB) was characterized. The ZmmtopVIB mutant plants exhibited normal vegetative growth but male and female sterility. DSB formation is abolished in mutant meiocytes. Despite normal assembly of axial elements, synapsis was severely affected and homologous pairing was disrupted in mutants. Importantly, we showed that bipolar spindle assembly was also affected in ZmmtopVIB, resulting in triad and polyad formation. Overall, our results demonstrate that ZmMTOPVIB plays critical roles in DSB formation and homologous recombination. In addition, the newly-discovered function of MTOPVIB in bipolar spindle assembly is likely conserved across different monocots. One-sentence summaryThe dual roles of MTOPVIB in regulating meiotic DSB formation and bipolar spindle assembly are evolutionarily conserved in monocot plants.

cell biology↗

bioRxiv2020

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a novel fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NTF3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NTF3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NTF3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NTF3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC+/-). Increasing NTF3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC+/- mice or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NTF3 is an important fat-derived neurotrophic factor regulating SNS innervation, energy metabolism and obesity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2018

Preclinical Modeling of Exposure to a Global Marine Bio Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory

Domoic Acid (DA) is a naturally-occurring marine neurotoxin that is increasingly recognized as an important public health issue. Prenatal DA exposure occurs through the maternal consumption of contaminated shellfish/finfish. To better understand the fetal risks associated with DA, we initiated a longitudinal, preclinical study focused on the reproductive and developmental effects of chronic, low-dose oral DA exposure. To this end, 32 adult female Macaca fascicularis monkeys were orally dosed with 0, 0.075 or 0.15 mg/kg/day DA on a daily basis prior to breeding and throughout breeding and pregnancy. The doses included the proposed human Tolerable Daily Intake (TDI) (0.075 mg/kg/day) for DA. Adult females were bred to nonexposed males. To evaluate development during early infancy, offspring were administered a Neonatal Assessment modeled after the human Neonatal Behavior Assessment Scale and a series of Visual Recognition Memory problems using the novelty paradigm. Results indicated that prenatal DA exposure did not impact early survival reflexes or responsivity to the environment. Findings from the recognition memory assessment, given between 1-2 months of age, showed that exposed and control infants demonstrated robust novelty scores when test problems were relatively easy to solve. Performance was not diminished by the introduction of delay periods. However, when more difficult recognition problems were introduced, the looking behavior of the 0.15 mg/kg DA group was random and infants failed to show differential visual attention to novel test stimuli. This finding suggests subtle but significant impairment in recognition memory and demonstrates that chronic fetal exposure to DA may impact developing cognitive processes.

pharmacology and toxicology↗

bioRxiv2018

Effects of Oral Domoic Acid Exposure on Maternal Reproduction and Infant Birth Characteristics in a Preclinical Nonhuman Primate Model

Domoic Acid (DA) is a naturally-occurring excitotoxin, produced by marine algae, which can bioaccumulate in shellfish and finfish. The consumption of seafood contaminated with DA is associated with gastrointestinal illness that, in the case of high DA exposure, can evolve into a spectrum of responses ranging from agitation to hallucinations, memory loss, seizures and coma. Because algal blooms that produce DA are becoming more widespread and very little is known about the dangers of chronic, low-dose exposure, we initiated a preclinical study focused on the reproductive and developmental effects of DA in a nonhuman primate model. To this end, 32 adult female Macaca fascicularis monkeys were orally exposed to 0, 0.075 or 0.15 mg/kg/day DA on a daily basis, prior to and during pregnancy. Females were bred to non-exposed males and infants were evaluated at birth. Results from this study provided no evidence of changes in DA plasma concentrations with chronic exposure. DA exposure was not associated with reproductive toxicity or adverse changes in the physical characteristics of newborns. However, in an unanticipated finding, our clinical observations battery revealed the presence of subtle neurological effects in the form of intentional tremors in the exposed adult females. While females in both dose groups displayed increased tremoring, the effect was dose-dependent and observed at a higher frequency in females exposed to 0.15 mg/kg/day. These results demonstrate that chronic, low-level exposure to DA is associated with injury to the adult CNS and suggest that current regulatory guidelines designed to protect human health may not be adequate for high-frequency shellfish consumers.\n\nHighlights1) Domoic acid acts as a tremoragen after chronic, low-dose oral exposure in adults.\n\n2) Exposure across pregnancy does not result in maternal reproductive toxicity.\n\n3) In-utero exposure does not adversely impact physical characteristics of exposed newborns.\n\n4) Current regulatory guidelines may not adequately protect high-frequency shellfish consumers from DA-induced neurological injury.

pharmacology and toxicology↗

bioRxiv2017

BMP signaling orchestrates a transcriptional network to control the fate of mesenchymal stem cells (MSCs)

Signaling pathways are used reiteratively in different developmental processes yet produce distinct cell fates through activating specific downstream transcription factors. In this study, we used tooth root development as a model to investigate how the BMP signaling pathway regulates specific downstream transcriptional complexes to direct the fate determination of multipotent mesenchymal stem cells (MSCs). We first identified the MSC population supporting mouse molar root growth as Gli1+ cells. Using a Gli1-mediated transgenic animal model, our results provide the first in vivo evidence that BMP signaling activity is required for the odontogenic differentiation of MSCs. Specifically, we identified transcription factors that are downstream of BMP signaling and are expressed in a spatially restricted pattern consistent with their potential involvement in determining distinct cellular identities within the dental mesenchyme. Finally, we found that overactivation of one key transcription factor, Klf4, associated with the odontogenic region, promotes odontogenic differentiation of MSCs. Collectively, our results demonstrate the functional significance of BMP signaling in regulating the fate of MSCs during root development and shed light on how BMP signaling can achieve functional specificity in regulating diverse organ development.\n\nSummary StatementBMP signaling activity is required for the lineage commitment of MSCs and transcription factors downstream of BMP signaling may determine distinct cellular identities within the dental mesenchyme.

developmental biology↗