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Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell-cycle behavior drive proliferation dynamics during T-cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell-cycle indicator mice to establish a quantitative high-resolution map of cell-cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell-cycle acceleration followed a 'stretch model', characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell-cycle phase dynamics during regeneration showed tailored adjustments of cell-cycle phase dynamics. Taken together, our results highlight intrathymic cell-cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.
High-resolution mapping of cell cycle dynamics during T-cell development and regeneration in vivo
(2024)
Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell cycle behavior drive proliferation dynamics during T-cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell cycle indicator mice to establish a quantitative high-resolution map of cell cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell cycle acceleration followed a ‘stretch model’, characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell cycle phase dynamics during regeneration showed tailored adjustments of cell cycle phase dynamics. Taken together, our results highlight intrathymic cell cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.
MAPK6/ERK3 is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary disfunction and by defects in function, activation and positive selection of T cells. To study the role of ERK3 in vivo, we generated mice carrying a conditional Erk3 allele with exon3 flanked by LoxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)-cre and a clear reduction of the protein kinase MK5 is detected, providing first evidence for the existence of the ERK3/MK5 signaling complex in vivo. In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile, do not display pulmonary hypoplasia, acute respiratory failure, abnormal T cell development, reduction of thymocyte numbers or altered T cells selection. Hence, ERK3 is dispensable for pulmonary and T-cell functions. The perinatal lethality, lung and T-cell defects of the previous ERK3 knockout mice are likely due to ERK3-unrelated effects of the inserted lacZ-neomycin-resistance-cassette. The knockout mouse of the closely related atypical MAPK ERK4/MAPK4 is also normal suggesting redundant functions of both protein kinases.
Background Reward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Methods Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).
Results Across social and monetary reward anticipation, whole-brain analyses (p<0.05, family-wise error-corrected) showed hypoactivation of the right ventral striatum (VS) in ASD. Further, region of interest (ROI) analysis across both reward types yielded hypoactivation in ASD in both the left and right VS. Across delivery of social and monetary reward, hyperactivation of the VS in individuals with ASD did not survive correction for multiple comparisons. Reward type by diagnostic group interactions, and a dimensional analysis of autism trait scores were not significant during anticipation or delivery. Levels of attention-deficit/hyperactivity disorder (ADHD) symptoms did not affect reward processing in ASD.
Conclusions Our results do not support current theories linking atypical social interaction in ASD to specific alterations in processing of social rewards. Instead, they point towards a generalized hypoactivity of VS in ASD during anticipation of both social and monetary rewards. We suggest that this indicates attenuated subjective reward value in ASD independent of social content and ADHD symptoms.