Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain.

Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNAnull mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring proteincoding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.

Development and regeneration of projection neuron subtypes of the cerebral cortex.

The idea of repairing damaged neuronal circuitry in the mammalian central nervous system (CNS) has challenged neuroscientists for centuries. This is mainly due to the notorious inability of neurons to regenerate and the unparalleled cellular diversity of the nervous system. In the mammalian cerebral cortex, one of the most complex areas of the CNS, multipotent neural stem and progenitor cells undergo progressive specification during development to generate the staggering variety of projection neuron subtypes that are found in the adult. How is this process orchestrated in the embryo? And, can developmental signals be used to regenerate projection neuron subtypes in the adult or in the dish? Here, we first provide an overview of the diversity and fate potential of neural progenitors of the cerebral cortex during development. Further, we discuss the plasticity of neural progenitors and the roles of intrinsic and extrinsic signals over progenitor fate. Finally, we discuss the relevance of developmental signals for efforts to direct the differentiation of pluripotent stem cells into specific types of cortical projection neurons for therapeutic benefit.

Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cells.

Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). The objective of this study was to investigate how tuberous sclerosis complex (TSC) 1 or TSC2 deficiency alters MMP expression and regulation. We studied immortalized cells that lack TSC2 derived from an angiomyolipoma of a patient with LAM, a TSC2 addback derivative, and murine embryonic fibroblast cells that lack Tsc1 or -2 and respective controls. Global gene expression analysis was performed in the angiomyolipoma and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared with their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be overexpressed in rapamycin-treated TSC2-deficient cells compared with TSC2(+) cells. We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin-insensitive, and that several genes exhibit similar patterns, suggesting that TSC1/TSC2-dependent, but mammalian target of rapamycin-independent, pathways may be involved in the pathogenesis of LAM.