Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo

Kuroda, Rintaro; Tominaga, Kaoru; Kasashima, Katsumi; Kuroiwa, Kenji; Sakashita, Eiji; Hayakawa, Hiroko; Kouki, Tom; Ohno, Nobuhiko; Kawai, Kensuke; Endo, Hitoshi

doi:10.1371/journal.pone.0255355

Cited by 5 publications

(1 citation statement)

References 63 publications

(67 reference statements)

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“…Apart from directly regulating expression of axon guidance molecules/receptors, NFIA also regulates mitochondrial respiration, providing neurons with the energy needed to establish connections with their targets. Transcription factors such as Tfam, Nrf1, NeuroD6, and Foxg1 have previously been linked to mitochondrial function during neurodevelopment [84][85][86][87][88][89] . However, of the transcription factors known to regulate motor neuron development (e.g.…”

Section: Postmitotic Expression Of Nfia Regulates Organization Of Spi...mentioning

confidence: 99%

Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA

Gauberg,

Moreno,

Jayaraman

et al. 2024

Preprint

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SUMMARYNeural circuits governing all motor behaviors in vertebrates rely on the proper development of motor neurons and their precise targeting of limb muscles. Transcription factors are essential for motor neuron development, regulating their specification, migration, and axonal targeting. While transcriptional regulation of the early stages of motor neuron specification is well-established, much less is known about the role of transcription factors in the later stages of maturation and terminal arborization. Defining the molecular mechanisms of these later stages is critical for elucidating how motor circuits are constructed. Here, we demonstrate that the transcription factor Nuclear Factor-IA (NFIA) is required for motor neuron positioning, axonal branching, and neuromuscular junction formation. Moreover, we find that NFIA is required for proper mitochondrial function and ATP production, providing a new and important link between transcription factors and metabolism during motor neuron development. Together, these findings underscore the critical role of NFIA in instructing the assembly of spinal circuits for movement.

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Section: Postmitotic Expression Of Nfia Regulates Organization Of Spi...mentioning

confidence: 99%

Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA

Gauberg,

Moreno,

Jayaraman

et al. 2024

Preprint

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Model-based inference of RNA velocity modules improves cell fate prediction

Aivazidis

Memi

Kleshchevnikov

et al. 2023

Preprint

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RNA velocity is a powerful paradigm that exploits the temporal information contained in spliced and unspliced RNA counts to infer transcriptional dynamics. Existing velocity models either rely on coarse biophysical simplifications or require extensive numerical approximations to solve the underlying differential equations. This results in loss of accuracy in challenging settings, such as complex or weak transcription rate changes across cellular trajectories. Here, we present cell2fate, a formulation of RNA velocity based on a linearization of the velocity ODE, which allows solving a biophysically accurate model in a fully Bayesian fashion. As a result, cell2fate decomposes the RNA velocity solutions into modules, which provides a new biophysical connection between RNA velocity and statistical dimensionality reduction. We comprehensively benchmark cell2fate in real-world settings, demonstrating enhanced interpretability and increased power to reconstruct complex dynamics and weak dynamical signals in rare and mature cell types. Finally, we apply cell2fate to a newly generated dataset from the developing human brain, where we spatially map RNA velocity modules onto the tissue architecture, thereby connecting the spatial organisation of tissues with temporal dynamics of transcription.

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Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells

Walter‐Manucharyan,

Martin,

Pfützner

et al. 2024

Dev Growth Differ

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Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8‐NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase‐γ by 2′‐3′‐dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.

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Loss of mitochondrial transcription factor A in neural stem cells leads to immature brain development and triggers the activation of the integral stress response in vivo

Cited by 5 publications

References 63 publications

Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA

Spinal motor neuron development and metabolism are transcriptionally regulated by Nuclear Factor IA

Model-based inference of RNA velocity modules improves cell fate prediction

Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells

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