DLK1 Promotes Neurogenesis of Human and Mouse Pluripotent Stem Cell-Derived Neural Progenitors Via Modulating Notch and BMP Signalling

Abstract

A better understanding of the control of stem cell maintenance and differentiation fate choice is fundamental to effectively realising the potential of human pluripotent stem cells in disease modelling, drug screening and cell therapy. Dlk1 is a Notch related transmembrane protein that has been reportedly expressed in several neurogenic regions in the developing brain. In this study, we investigated the ability of Dlk1 in modulating the maintenance and differentiation of human and mouse ESC-derived neural progenitors. We found that DLK1, either employed as an extrinsic factor, or via transgene expression, consistently promoted the generation of neurons in both the mouse and human ESC-derived neural progenitors. DLK1 exerts this function by inducing cell cycle exit of the progenitors, as evidenced by an increase in the number of young neurons retaining BrdU labelling and cells expressing the cycling inhibitor P57Kip2. DLK1 antagonised the cell proliferation activity of Notch ligands Delta 1 and Jagged and inhibited Hes1-mediated Notch signaling as demonstrated by a luciferase reporter assay. Interestingly, we found that DLK1 promotes the neurogenic potential of human neural progenitor cells via suppression of Smad activation when they are challenged with BMP. Together, our data demonstrate for the first time a regulatory role for DLK1 in human and mouse neural progenitor differentiation and establish an interaction between DLK1 and Hes1-mediated Notch signaling in these cells. Furthermore, this study identifies DLK1 as a novel modulator of BMP/Smad signalling.

Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours

“…Our previous observation of DLK1 expression in immature and progenitor LCs is consistent with the presence of DLK1 in undifferentiated cells in various endocrine tissues (26,27,28). The high expression of DLK1 in TART may suggest that these nodules develop from an immature or even fetal cell type.…”

Transcriptome analysis reveals transmembrane targets on transplantable midbrain dopamine progenitors

“…Transcriptional profiling of this cell fraction identified a range of genes encoding for transcription factors and other transcriptional regulators, components of signaling pathways, and secreted molecules. Several of these genes have been identified and verified in previous gene expression studies (Dmrta1 and Dlk1) (14,15) or have well-established roles in mDA neurogenesis and differentiation (TH, Lmx1a, Nurr1, En1, and Foxa2) (reviewed in refs. 16 and 17).…”

Delta-Like 1 Homologue (DLK1) Protein in Neurons of the Arcuate Nucleus That Control Weight Homeostasis and Effect of Fasting on Hypothalamic DLK1 mRNA

“…Notch signaling factors such as Hes1 and Mash1 are present in hypothalamic progenitors that give rise to Arc neurons [40,41,42,43] and Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons [44]. DLK1 has been reported to promote neurogenesis of neural progenitors [45,46], branching morphogenesis via Notch signaling [47], and to be associated with dopaminergic differentiation in the midbrain [48]. Based on these results, it is likely that DLK1, expressed by the vast majority of neurons in the Arc, is involved in the development and synaptic plasticity of neurons in the Arc.…”