Biology subjects

Beaulieu, M.

Publications and source records attributed to Beaulieu, M..

4 recordsLinked to original sources

bioRxiv2020

Groucho/TLE opposes axial to hypaxial motor neuron development

Spinal cord motor neuron diversity and the ensuing variety of motor circuits allow for the processing of elaborate muscular behaviours such as body posture and breathing. Little is known, however, about the molecular mechanisms behind the specification of axial and hypaxial motor neurons controlling postural and respiratory functions respectively. Here we show that the Groucho/TLE (TLE) transcriptional corepressor is a multi-step regulator of axial and hypaxial motor neuron diversification in the developing spinal cord. TLE first promotes axial motor neuron specification at the expense of hypaxial identity by cooperating with non-canonical WNT5A signalling within the motor neuron progenitor domain. TLE further acts during post-mitotic motor neuron diversification to promote axial motor neuron topology and axonal connectivity whilst suppressing hypaxial traits. These findings provide evidence for essential and sequential roles of TLE in the spatial and temporal coordination of events regulating the development of motor neurons influencing posture and controlling respiration. HIGHLIGHTSO_LIGroucho/TLE mediates non-canonical WNT signalling in developing motor neurons C_LIO_LINon canonical WNT:TLE pathway regulates thoracic motor neuron diversification C_LIO_LITLE promotes axial while inhibiting hypaxial motor neuron development C_LIO_LITLE influences developing motor neuron topology and muscle innervation C_LI IN BRIEFSalin-Cantegrel et al use in ovo engineered approaches to show that a non-canonical WNT:TLE pathway coordinates temporally and spatially separated elements of motor neuron diversification, repressing hypaxial motor neuron development to promote the axial fate. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/986323v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@e2d96dorg.highwire.dtl.DTLVardef@130baf4org.highwire.dtl.DTLVardef@41fa32org.highwire.dtl.DTLVardef@190ebd3_HPS_FORMAT_FIGEXP M_FIG TLE contribution to the development of thoracic somatic motor columns Progenitor cells in the ventral pMN domain are exposed to higher concentrations of non-canonical WNTs and express more TLE. Cooperation of non-canonical WNTs and TLE renders ventral pMN progenitors refractory to a respiratory MN fate, thereby contributing to the separation of MMC and RMC MN lineages. Differentiating MNs that maintain high TLE expression also maintain LHX3 expression, adopt axial motor neuron topology and connect to axial muscles. TLE activity in differentiating MMC MNs prevents the acquisition of respiratory MN topology and innervation traits. C_FIG

neuroscience↗

bioRxiv2020

Robust Production of Uniform Human Cerebral Organoids from Pluripotent Stem Cells

Human cerebral organoid (hCO) models offer the opportunity to understand fundamental processes underlying human specific cortical development and pathophysiology in an experimentally tractable system. While diverse methods to generate brain organoids have been developed, a major challenge has been the production of organoids with reproducible cell type heterogeneity and macroscopic morphology. Here, we directly addressed this problem by establishing a robust production pipeline to generate morphologically consistent (ie uniform) hCOs and achieve a success rate of >80%. These hCOs include both a radial glial stem cell compartment and electrophysiologically competent mature neurons. Moreover, we show using immunofluorescence microscopy and single cell profiling, that individual organoids display reproducible cell type compositions that are conserved upon extended culture. We expect that application of this method will provide new insights into brain development and disease processes.

neuroscience↗

bioRxiv2019

Differential oxidative costs of locomotory and genital damage in an orb-weaving spider

In animals that regularly experience tissue loss, physiological responses may have evolved to overcome the related costs. Changes in oxidative status may reflect such self-maintenance mechanisms. Here, we investigated how markers of oxidative status varied in female orb-weaving spiders (Larinia jeskovi) by mimicking two distinct types of tissue loss they may naturally encounter: damage to their locomotory system and damage to their external genital structure, as inflicted by males to females during copulation (external female genital mutilation). Damage to the locomotory system resulted in a significant shift in the oxidative status reflecting investment into self-maintenance. In contrast, the loss of the genital structure did not result in quantitative changes of oxidative markers. The lack of response to genital mutilation suggests that genital mutilation is physiologically not costly for female spiders. The cost incurred to females rather arises from genital mutilation preventing the females from remating with another male.

evolutionary biology↗

bioRxiv2019

CRISPR/Cas9 mediated intersectional knockout of GSK3β in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation

BackgroundGlycogen synthase kinase 3{beta} (GSK3{beta}) regulates neurodevelopment, synaptic plasticity as well as mood, cognition, social interaction, and depressive-like behaviors. Inhibition of GSK3{beta} is a shared consequence of treatment by lithium, SSRIs, ketamine and antipsychotics. GSK3{beta} activity is regulated by dopamine D2 receptor signaling and can be inhibited by psychoactive drugs in a D2 receptor dependent manner. Functions of GSK3{beta} in striatal D2 neurons has been studied extensively. However, GSK3{beta} is ubiquitously expressed in the brain and D2 receptor expressing cells are distributed as a mosaic in multiple cortical regions. This complicates the interrogation of GSK3{beta} functions in cortical D2 cells in a circuit defined manner using conventional animal models.\n\nMethodsWe have used a CRISPR/Cas9 mediated intersectional approach to achieve targeted deletion of GSK3{beta} in D2 expressing neurons of the adult medial prefrontal cortex (mPFC).\n\nResultsIsolation and analysis of ribosome associated RNA specifically from mPFC D2 neurons lacking GSK3{beta} demonstrated large scale translatome alterations. Deletion of GSK3{beta} in mPFC D2 neurons revealed its contribution to anxiety-related, cognitive, and social behaviors.\n\nConclusionsOur results underscore the viability of intersectional knockout approach to study functions of a ubiquitous gene in a network defined fashion while uncovering a contribution of GSK3{beta} expressed in mPFC D2 neurons in the regulation of behavioral dimensions related to mood and emotions. This advances our understanding of GSK3{beta} action at a brain circuit level and can potentially lead to the development of circuit selective therapeutics.

neuroscience↗