Pluripotent stem cells possess a tremendous potential for the treatment of many diseases because of their capacity to differentiate into a variety of cell lineages. However, they provide little promise for muscle-related diseases, mainly because of the lack of small molecule inducers to efficiently direct myogenic conversion. Retinoic acid, acting through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), affects stem cell fate determination in a concentration-dependent manner, but it only has a modest efficacy on the commitment of ES cells into skeletal muscle lineage. The RXR is very important for embryonic development but is generally considered to act as a silent partner of RAR in a non-permissive mode. In this study, we have examined whether activation of the RXR by rexinoid or RXR-specific signaling play a role in the specification of stem cells into muscle lineage. Our findings demonstrate that mouse ES cells generate skeletal myocytes effectively upon treatment with rexinoid at the early stage of differentiation and that on a molecular level, rexinoid-enhanced myogenesis simulates the sequential events observed in vivo. Moreover, RXR-mediated myogenic conversion requires the function of β-catenin but not RAR. Our studies establish the feasibility of applying the RXR agonist in cell-based therapies to treat muscle-related diseases. The aptitude of mouse ES cells to generate skeletal myocytes following rexinoid induction also provides a model system to study the convergence of different signaling pathways in myogenesis.

Skeletal myogenesis is an intricate process coordinated temporally by multiple myogenic regulatory factors (MRF) including Myf5, which is the first MRF expressed and marks the commitment of skeletal muscle lineage. The expression of Myf5 gene during early embryogenesis is controlled by a set of enhancer elements, and requires the histone acetyltransferase (HAT) activity of transcriptional coactivator p300. However, it is unclear as to how different regulatory signals converge at enhancer elements to regulate early Myf5 gene expression, and if p300 is directly involved. We show here that p300 associates with the Myf5 early enhancer at the early stage of stem cell differentiation, and its HAT activity is important for the recruitment of β-catenin to this early enhancer. In addition, histone H3-K27 acetylation, but not H3-K9/14, is intimately connected to the p300 HAT activity. Thus, p300 is directly involved in the regulation of the Myf5 early enhancer, and is important for specific histone acetylation and transcription factor recruitment. This connection of p300 HAT activity with H3-K27 acetylation and β-catenin signalling during myogenic differentiation in vitro offers a molecular insight into the enhancer-elements participation observed in embryonic development. In addition, pluripotent stem cell differentiation is a valuable system to dissect the signal-dependent regulation of specific enhancer element during cell fate determinations.

Breast cancer is the most common cancer in women, with 15%–25% of those tumours overexpressing the human epidermal growth factor receptor 2 (her2), which is associated with more aggressive disease. On rare occasions, patients present with a paraneoplastic syndrome months to years before their cancer diagnosis. Paraneoplastic cerebellar degeneration (pcd) is associated with fewer than 1% of cancers and is strongly associated with breast and gynecologic malignancies. Anti-Yo antibody is the antibody most frequently identified with the syndrome, and it is associated with a very poor prognosis. Recent studies have implicated a relationship between overexpression of her2 and anti-Yo–mediated pcd. Current pcd treatments include tumour removal, chemotherapy, targeted therapy, and immune-suppressive treatments. Outcomes of pcd are typically poor, and no guidelines for treatment currently exist. Early recognition followed by rapid initiation of treatment remains the cornerstone of therapy.Here, we present a case of anti-Yo-antibody pcd secondary to estrogen and progesterone receptor–negative, her2-positive breast cancer. Despite treatment with mastectomy, chemotherapy, and her2-targeted therapy, no significant neurologic improvement was achieved, and cerebellar cognitive affective syndrome subsequently developed.

No abstract