cyclin-d1 and Demyelinating-Diseases

To analyse whether the expression of apoptotic transcripts is associated with the conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS). Eleven candidate transcripts belonging to the death receptor pathway, BCL-2, the inflammasome complex and NF-ΚB family were studied in the nonconverting and converting CIS patients during the four-year follow-up period. Conversion to MS was associated with marked variability in the expression of proapoptotic genes that were linked to TGF-B1 gene levels. The predominant expression of proapoptotic genes in patients with CIS suggests an increased potential to undergo apoptosis with the goal of terminating immune responses and regulating immune system homeostasis.

Topics: Adult; Apoptosis; CARD Signaling Adaptor Proteins; Caspase 1; Cohort Studies; Cyclin D1; Cytokines; Cytoskeletal Proteins; Demyelinating Diseases; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; NF-kappa B; Receptors, Death Domain; Signal Transduction; Transforming Growth Factor beta1

MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes, including differentiation, proliferation, and cancer. Here, we study the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzyme Dicer1. We reveal that both male and female mice lacking Dicer1 in SC (Dicer1 conditional knock-outs) display a severe neurological phenotype resembling congenital hypomyelination. Ultrastructural analyses show that many SC lacking Dicer1 are stalled in differentiation at the promyelinating state and fail to myelinate axons. Gene expression analyses reveal a failure to extinguish genes characteristic of the undifferentiated state such as Sox2, Jun, and Ccnd1. Sox2 and Jun are well characterized negative regulators of SC differentiation. Consistent with Sox2/Jun maintenance, Egr2, a master regulator of the myelinating program, is drastically downregulated and likely accounts for the myelination defect. We posit a model wherein microRNAs are critical for downregulation of antecedent programs of gene expression. In SC differentiation, this is particularly relevant in the key developmental transition from a promyelinating to myelinating SC.

Topics: Animals; Animals, Newborn; Bromodeoxyuridine; Cell Differentiation; Cyclin D1; DEAD-box RNA Helicases; Demyelinating Diseases; Disease Models, Animal; Early Growth Response Protein 2; Endoribonucleases; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Indoles; Male; Mice; Mice, Knockout; MicroRNAs; Microscopy, Electron, Transmission; Oligonucleotide Array Sequence Analysis; Proto-Oncogene Proteins c-jun; Ribonuclease III; Schwann Cells; Sciatic Nerve; SOXB1 Transcription Factors