Biology subjects

Fernandez-Suarez, D.

Publications and source records attributed to Fernandez-Suarez, D..

4 recordsLinked to original sources

bioRxiv2022

Dopamine and ALK4 signaling synergize to induce PCBP1-mediated alternative splicing of FosB and sustained behavioral sensitization to cocaine

{Delta}FosB, an alternative spliced product of FosB, is an essential component of dopamine-induced reward pathways and a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of {Delta}FosB mRNA in medium spiny neurons (MSNs) of the nucleus-accumbens (NAc) through activation of the RNA binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired {Delta}FosB mRNA induction and nuclear translocation of {Delta}FosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Importantly, ALK4 was required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for {Delta}FosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.

neuroscience↗

bioRxiv2021

AraC binds the p75NTR transmembrane domain to induce neurodegeneration in mature neurons.

BackgroundCytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer including acute myeloid leukaemia. However, after high dose AraC chemotherapy regime, patients develop severe neurotoxicity and neurodegeneration in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells, however, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesized that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukemia patients undergoing AraC treatment. MethodsTo determine the role of AraC-p75NTR signalling in degeneration of mature cerebellar granule neurons, we used primary cultures from p75NTR knockout and p75NTRCys259 mice. Evaluation of neurodegeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the direct interaction between AraC and p75NTR, we performed isothermal dose response-cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. ResultsWe show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, AraC binds to Proline 252 and Cysteine 256 of the p75NTR transmembrane domain and selectively uncouples p75NTR from the NF{kappa}B survival pathway. This in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. ConclusionOur findings identify p75NTR as a novel molecular target to develop treatments to counteract AraC-mediated neurodegeneration.

cell biology↗

bioRxiv2021

Adult medial habenula neurons require GDNF receptor GFRalpha1 for synaptic stability and function

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatio-temporally controlled Cre-mediated recombination in adult mice, we found that the GDNF receptor alpha 1 (GFR1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFR1 in the mouse brain, and acute ablation of GFR1 results in loss of septo-habenular and habenulo-interpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and opto-genetic studies in mice lacking GFR1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index of AMPARs, suggesting reduced Ca2+-permeability. Further biochemical and proximity ligation assay studies defined the presence of GluA1/GluA2 (Ca2+-impermeable) as well as GluA1/GluA4 (Ca2+-permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits in mHb neurons lacking GFR1. Finally, acute loss of GFR1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFR1 in the maintenance and function of adult glutamatergic synapses, and reveal a potential new mechanism for regulating synaptic plasticity in the septo-habenulo-interpeduncular pathway and attuning of anxiety and fear behaviors.

neuroscience↗

bioRxiv2019

Activin receptor ALK4 coordinates extracellular signals and intrinsic transcriptional programs to regulate development of cortical somatostatin interneurons

Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific loses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

neuroscience↗