Spatial and transcriptional heterogeneity of β-cell neogenesis revealed by a time-resolved reporter system

While pancreatic β cells have been shown to originate from endocrine progenitors in ductal regions, it remains unclear precisely where β cells emerge and which transcripts define newborn β cells. Here, we used a mouse model “Ins1-GFP;Timer” that provides spatial information during β-cell neogenesis with high temporal resolution. Fluorescent imaging demonstrated that, as expected, some newborn β cells arise close to the ducts; unexpectedly, all the others arise away from the ducts and adjacent to blood vessels. Single-cell RNA-sequencing (scRNA-seq) demonstrated five distinct populations of newborn β cells, confirming the spatial heterogeneity of β-cell neogenesis, and integration analysis with scRNA-seq of hESC-derived β-like cells uncovered transcriptional similarity with the data in mouse β cells. Thus, the combination of time-resolved histological imaging with single-cell transcriptional mapping demonstrated novel features of spatial and transcriptional heterogeneity in β-cell neogenesis, which will lead to a better understanding of β-cell differentiation for future cell therapy.

Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.