Adam, M. | Search bioRxiv

bioRxiv2018

Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus

The uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. The Hoxa10 and Hoxa11 genes have previously been shown to play essential roles in uterus development and function. In this report we show that the Hoxc9,10,11 genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.\n\nSummary statementA single cell RNA-seq study of the developing mouse uterus defines cellular heterogeneities, lineage specific gene expression programs and perturbed pathways in Hox9,10,11 mutants.

developmental biology↗

bioRxiv2018

Ehmt1 forebrain haploinsufficiency leads to impaired memory, sensory gating and information processing

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders (NDDs). Haploinsufficiency of EHMT1, encoding a histone methyl-transferase, is associated with several NDDs, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to NDDs. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity (MMN). The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the NDDs associated with EHMT1 haploinsufficiency.

neuroscience↗