Biology subjects

Greenfield, A.

Publications and source records attributed to Greenfield, A..

3 recordsLinked to original sources

bioRxiv2022

Transient, developmental exposure to patient-derived anti-NMDA receptor autoantibodies causes long-term axonal and behavioral defects

NMDA receptor mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific monoclonal antibody (mAb) during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced inter-hemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/510196v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@37f452org.highwire.dtl.DTLVardef@1894e46org.highwire.dtl.DTLVardef@171f954org.highwire.dtl.DTLVardef@1a81742_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Origin, specification and differentiation of a rare supporting-like lineage in the developing mouse gonad

Gonadal sex determination represents a unique model for studying cell fate decisions. However, a complete understanding of the different cell lineages forming the developing testis and ovary remains elusive. Here, we investigated the origin, specification and subsequent sex-specific differentiation of a previously uncharacterized population of supporting-like cells (SLC) in the developing mouse gonads. The SLC lineage is closely related to the coelomic epithelium and specified as early as E10.5, making it the first somatic lineage to be specified in the bipotential gonad. SLC progenitors are localized within the genital ridge at the interface with the mesonephros and initially co-express Wnt4 and Sox9. SLCs become sexually dimorphic around E12.5, progressively acquire a Sertoli- or granulosa-like identity and contribute to the formation of the rete testis and rete ovarii. Finally, we found that WNT4 is a crucial regulator of the SLC lineage and is required for the formation of the rete testis. TeaserDescription of an uncharacterized multipotent gonadal cell lineage involved in testis and ovary development

developmental biology↗

bioRxiv2018

Single-cell transcriptomics of the mouse gonadal soma reveals the establishment of sexual dimorphism in distinct cell lineages

Sex determination is a unique process that allows the study of multipotent progenitors and their acquisition of sex-specific fates during differentiation of the gonad into a testis or an ovary. Using time-series single-cell RNA sequencing (scRNA-seq) on ovarian Nr5a1-GFP+ somatic cells during sex determination, we identified a single population of early progenitors giving rise to both pre-granulosa cells and potential steroidogenic precursor cells. By comparing time-series scRNA-seq of XX and XY somatic cells, we demonstrate that the supporting cells emerge from the early progenitors with a non-sex-specific transcriptomic program, before pre-granulosa and Sertoli cells acquire their sex-specific identity. In XX and XY steroidogenic precursors similar transcriptomic profiles underlie the acquisition of cell fate, but with a delay in XX cells. Our data provide a novel framework, at single-cell resolution, for further interrogation of the molecular and cellular basis of mammalian sex determination.

developmental biology↗