Splicing is fundamental to gene expression in all eukaryotic organisms. Indeed, aberrant splicing is associated with many inherited diseases such as spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), myotonic dystrophy (DM), microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) and others. The process of splicing is co-transcriptional and is executed by the spliceosome of which there are two types, i.e. the major and the minor spliceosome. As the name suggests, majority of the splicing in humans is executed by the major spliceosome, but there are <2% of the genes in humans that have at least one intron that it cannot splice. This minor subset of introns is spliced by the aptly named minor spliceosome. It must be noted that the efficiency of minor intron splicing is lower than its major introns and is attributed to low levels of these snRNAs. Moreover, these minor introns are found in ~450 human genes that execute various functions in the cell. Therefore, the function of the minor spliceosome including its inefficient splicing can have a profound impact on expression of these genes. Yet, the role of these introns and its spliceosome as it relates to mammalian cortical development has not been explored. Thus, our overall objective is to understand the role of minor introns and the minor spliceosome in neocortical development and disease. Recently it was discovered that infants born with devastating disease MOPD1 is caused by mutations altering the function of the minor spliceosome. Here we report a U11 conditional knockout mouse that inactivates the spliceosome in the developing cortex that recapitulates one of the cardinal features i.e., microcephaly in MOPD1. Therefore in this mouse model of microcephaly, we will be able to determine how minor spliceosome informs cortical development. Specifically, we will employ custom microarray and RNAseq to capture genes regulated by the minor spliceosome. This in turn will reveal the specific step(s) of the cell cycle that is affected in the absence of a functions U11 snRNA. Understanding regulation of cell cycle has long been a major goal in developmental biology and in stem cell biology as it is the foundation of developing tissue. Moreover, failure to precisely control cell cycle can have drastic developmental defects such as those observed in MOPD1 and infant glioblastomas. While these issues have been under intense investigation, the role of minor spliceosome has remained unexplored. Hew we show that minor spliceosome is indeed crucial for neocortical development and our proposed experiments will shed further insights on the manner in which it regulates cell cycle and neocortical development.

Public Health Relevance

Here we recapitulate microcephaly observed in patients with microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) by ablating U11 snRNA, which is required for minor spliceosome function, in the developing mouse neocortex. Our study will reveal the role of minor spliceosome in normal/aberrant cortical development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurogenesis and Cell Fate Study Section (NCF)
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Riddle, Robert D
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University of Connecticut
Schools of Arts and Sciences
United States
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Baumgartner, Marybeth; Olthof, Anouk M; Aquino, Gabriela S et al. (2018) Minor spliceosome inactivation causes microcephaly, owing to cell cycle defects and death of self-amplifying radial glial cells. Development 145: