Regulatory principles and mechanisms governing the onset of random X-chromosome inactivation

Schwämmle, Till; Schulz, Edda G.

doi:10.1016/j.gde.2023.102063

Cited by 14 publications

(8 citation statements)

References 70 publications

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“…It is important to note that the transdominant effects on CO 2 sensitivity that we describe for some of the Cx32 mutations remain compatible with the strong evidence that shows CMTX being much less severe in females compared to males. As mentioned above, X chromosome inactivation ensures that in females each cell expresses genes from only one copy of the X chromosome (Gartler and Riggs, 1983;Lyon, 1988;Schwämmle and Schulz, 2023). For the same reason, as X chromosome inactivation occurs at random, in a nerve bundle of a heterozygous female (with one wild type and one mutant Cx32 allele) around half of the Schwann cells will express only the wild type gene and the remainder the mutant gene (Scherer et al, 1998).…”

Section: Comparison To Mutations Of Cx26mentioning

confidence: 99%

X-linked Charcot Marie Tooth mutations alter CO2 sensitivity of connexin32 hemichannels

Butler,

Dale

2023

Front. Cell. Neurosci.

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Connexin32 (Cx32) is expressed in myelinating Schwann cells. It forms both reflexive gap junctions, to facilitate transfer of molecules from the outer to the inner myelin layers and hemichannels at the paranode to permit action potential-evoked release of ATP into the extracellular space. Loss of function mutations in Cx32 cause X-linked Charcot Marie Tooth disease (CMTX), a slowly developing peripheral neuropathy. The mechanistic links between Cx32 mutations and CMTX are not well understood. As Cx32 hemichannels can be opened by increases in PCO2, we have examined whether CMTX mutations alter this CO2 sensitivity. By using Ca2+ imaging, dye loading and genetically encoded ATP sensors to measure ATP release, we have found 5 CMTX mutations that abolish the CO2 sensitivity of Cx32 hemichannels (A88D, 111–116 Del, C179Y, E102G, V139M). Others cause a partial loss (L56F, R220Stop, and R15W). Some CMTX mutations have no apparent effect on CO2 sensitivity (R15Q, L9F, G12S, V13L, V84I, W133R). The mutation R15W alters multiple additional aspects of hemichannel function including Ca2+ and ATP permeability. The mutations that abolish CO2 sensitivity are transdominant and abolish CO2 sensitivity of co-expressed Cx32WT. We have shown that Schwannoma RT4 D6P2T cells can release ATP in response to elevated PCO2 via the opening of Cx32. This is consistent with the hypothesis that the CO2 sensitivity of Cx32 may be important for maintenance of healthy myelin. Our data, showing a transdominant effect of certain CMTX mutations on CO2 sensitivity, may need to be taken into account in any future gene therapies for this condition.

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Section: Comparison To Mutations Of Cx26mentioning

confidence: 99%

X-linked Charcot Marie Tooth mutations alter CO2 sensitivity of connexin32 hemichannels

Butler,

Dale

2023

Front. Cell. Neurosci.

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“…This constitution is established at fertilization, so that post-meiotic sperm would normally be 50:50 X-bearing to Y-bearing, so approximately equal numbers of male and female embryos are produced by random fertilization. Gene dosage control is critical for correct functioning of many genes and is one of the reasons cited for the observed random inactivation of one of the two X chromosomes in XX individuals of all eutherian mammals [ 19 , 20 ]. X chromosome inactivation (XCI) arises by an epigenetic process involving the production and persistence of a long non-coding RNA, named XIST (X inactive-specific transcript).…”

Section: Random X-chromosome Inactivation In XX Individualsmentioning

confidence: 99%

Stochasticity in genetics and gene regulation

van Heyningen

2024

Phil. Trans. R. Soc. B

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Development from fertilized egg to functioning multi-cellular organism requires precision. There is no precision, and often no survival, without plasticity. Plasticity is conferred partly by stochastic variation, present inherently in all biological systems. Gene expression levels fluctuate ubiquitously through transcription, alternative splicing, translation and turnover. Small differences in gene expression are exploited to trigger early differentiation, conferring distinct function on selected individual cells and setting in motion regulatory interactions. Non-selected cells then acquire new functions along the spatio-temporal developmental trajectory. The differentiation process has many stochastic components. Meiotic segregation, mitochondrial partitioning, X-inactivation and the dynamic DNA binding of transcription factor assemblies—all exhibit randomness. Non-random X-inactivation generally signals deleterious X-linked mutations. Correct neural wiring, such as retina to brain, arises through repeated confirmatory activity of connections made randomly. In immune system development, both B-cell antibody generation and the emergence of balanced T-cell categories begin through stochastic trial and error followed by functional selection. Aberrant selection processes lead to immune dysfunction. DNA sequence variants also arise through stochastic events: some involving environmental fluctuation (radiation or presence of pollutants), or genetic repair system malfunction. The phenotypic outcome of mutations is also fluid. Mutations may be advantageous in some circumstances, deleterious in others. This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.

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“…29 Intriguingly Xist, which is totally absent from somatic translatomes, is found in central terminals and enriched in female mice. 25 This gene, crucial for X-inactivation, may associate with polysomes like other ncRNAs but its mechanisms of action remain uncertain. Nhsl2 is a cytoplasmic calcium-binding protein 20-fold upregulated in females that is linked to Nance-Horan syndrome.…”

Section: Advillin-cre; Egfpl10a Somatic and Terminal Translatomes Are...mentioning

confidence: 99%

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

Bangash,

Cubuk,

Iseppon

et al. 2024

Preprint

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The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

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Regulatory principles and mechanisms governing the onset of random X-chromosome inactivation

Cited by 14 publications

References 70 publications

X-linked Charcot Marie Tooth mutations alter CO2 sensitivity of connexin32 hemichannels

X-linked Charcot Marie Tooth mutations alter CO2 sensitivity of connexin32 hemichannels

Stochasticity in genetics and gene regulation

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

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