Gonzales, J. P. | bioRxiv Science

bioRxiv2026

Astrocyte-oligodendrocyte crosstalk dependent myelination via secreted protein YKL40

Although oligodendrocyte differentiation and myelin formation are inherent properties of oligodendrocyte progenitor cells (OPCs) that are guided by intrinsic transcriptional and epigenetic programs, this process in the brain is finely regulated by signals coming from other cells, including astrocytes. Here, we identified the astrocyte secreted protein YKL40 at the center of astrocyte-OPC cross-communication and myelination in the developing brain. We find that YKL40 is expressed by astrocytes within white matter areas in the developing brain, coinciding with the OPC differentiation and myelination. Deletion of YKL40 in astrocytes showed delayed developmental myelination and reduced OPC proliferation. Interestingly, coculture with OPCs in vitro specifically induces YKL40 expression in astrocytes, which in turn promotes OPC differentiation and OPC proliferation. Mechanistically, purified YKL40 significantly induced the expression of transcription factors Olig2 and MYRF (Myeline regulatory factor) in OPCs. Therefore, we identified a novel mechanism of OPC-astrocyte crosscommunication dependent myelination by astrocytic YKL40 in the developing brain.

neuroscience↗

bioRxiv2026

Aberrant neuronal differentiation and splicing defects in Congenital Myotonic Dystrophy (DM1) iPSC models

Myotonic Dystrophy type 1 (DM1) is an autosomal multisystem disorder manifested due to unstable CTG nucleotide repeat expansion within the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Although progress towards understanding of molecular pathogenesis in muscle and heart has been made, the pathways that affect the brain in DM1 is fundamentally unknown. In addition, the congenital DM1 manifest even more complicated brain abnormalities. Despite the wealth of existing cellular and animal models, iPSCs based studies are being fostered as they replicate the human model more closely to the disease. In view of this context, we set out to characterize the differentiation potential of congenital DM1 patient derived iPSC lines towards neuronal cells. Using neurogenin2 (NGN2) induced direct reprogramming of iPSCs into neurons and chemically defined media-induced neural induction protocol, we find that congenital DM1 mutant iPSC derived neurons exhibited precocious differentiation, as evidenced by their expression of pan-neuronal markers TUJ1 and Map2, along with increased processes extension and neurite length. Moreover, unbiased RNA sequencing analyses and qPCR validation revealed precocious and enhanced expression of several neurogenic transcription factors including, Ascl1, NeuroG2, and NeuroD1. Furthermore, immunofluorescence imaging of MBNL1 and MBNL2, RNA-splicing factors, displayed enhanced nuclear aggregations, a hallmark of the DM1 disease, in the mutant lines. Moreover, investigation of RNA splicing events identified mis-splicing in many important genes/transcripts including RMST, ANK3 and MBD1 during the neural conversion of congenital DM1 lines. These studies reveal novel paradigms that may contribute to neurological pathogenesis in CDM1 patients. These studies also provide a strong foundation for future mechanistic investigation aimed at understanding CDM1 pathology and may open new avenues for the development of gene therapy approaches for individuals with DM1.

neuroscience↗