Biology subjects

Merl-Pham, J.

Publications and source records attributed to Merl-Pham, J..

3 recordsLinked to original sources

bioRxiv2022

Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies

The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs decrease. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/479353v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@5712f9org.highwire.dtl.DTLVardef@9eb133org.highwire.dtl.DTLVardef@83b7b2org.highwire.dtl.DTLVardef@1912e5c_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen 3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3CTT mice showed a recessive dystonia-like phenotype. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3CTT mice have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3CTT mice was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control. SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.

neuroscience↗

bioRxiv2021

Epiblast morphogenesis is controlled by selective mRNA decay triggered by LIN28A relocation

The embryonic progression from naive to primed pluripotency is accompanied by the rapid decay of pluripotency-associated mRNAs and a concomitant radical morphogenetic sequence of epiblast polarization, rosette formation and lumenogenesis. The mechanisms triggering and linking these events remain poorly understood. Guided by machine learning and metabolic RNA sequencing, we identified RNA binding proteins (RBPs), especially LIN28A, as primary mRNA decay factors. Using mRNA-RBP interactome capture, we revealed a dramatic increase in LIN28A mRNA binding during the naive-rosette-primed pluripotency transition, driven by its nucleolar-to-cytoplasmic translocation. Cytoplasmic LIN28A binds to 3UTRs of pluripotency-associated mRNAs to directly stimulate their decay and drive lumenogenesis. Accordingly, forced nuclear retention of LIN28A impeded lumenogenesis, impaired gastrulation, and caused an unforeseen embryonic multiplication. Selective mRNA decay, driven by nucleo-cytoplasmic RBP translocation, therefore acts as an intrinsic mechanism linking cell identity switches to the control of embryonic growth and morphogenesis.

developmental biology↗