Academic journal article Genetics

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

Academic journal article Genetics

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

Article excerpt

MicroRNAs (miRNAs) are a class of 22-nucleotide noncoding RNA molecules that function as sequencespecific guides. They direct an Argonaute (Ago) proteincontaining RNA-induced silencing complex (RISC) to target messenger RNAs (mRNAs) (Hutvagner and Zamore 2002; Mourelatos et al. 2002) by way of Watson-Crick pairing of the miRNA seed sequence to complementary elements usually found within the 39 untranslated region of target mRNAs (Bartel 2009). This results in translational repression and/or mRNA destabilization and decay (see Iwakawa and Tomari 2015 for a recent review). MicroRNAs are first transcribed as long primary transcripts (pri-miRNAs) with a characteristic hairpin-like secondary structure (Mourelatos et al. 2002). In the canonical bioprocessing pathway, this hairpin-like structure is recognized by the microprocessor-enzyme complex, through Ribonuclease 3 (protein Drosha) and Microprocessor complex subunit DGCR8 (Lee et al. 2003; Denli et al. 2004; Han et al. 2004), which cleaves the pri-miRNA into an 70-nucleotide precursor miRNA (pre-miRNA). The pre-miRNA is further processed, once exported to the cytoplasm (Bohnsack et al. 2004; Lund et al. 2004), by the RNase III enzyme Dicer, into a mature 22-nucleotide RNA duplex with 2-nucleotide overhangs at both 39 hydroxyl termini (Blaszczyk et al. 2001; Hutvagner et al. 2001). The endoribonuclease Dicer, in addition to cleaving pre-miRNAs, participates in the loading of miRNAs into RISC (Chendrimada et al. 2005). Both the endoribonuclease Dicer and protein Drosha are thought to cleave double-stranded RNAs by forming an intramolecular pseudodimer between two tandem RNase III domains (a/b) (Han et al. 2004; Zhang et al. 2004). In mice, a lysine residue (K1790) within the ribonuclease (RNase) IIIb domain of endoribonuclease Dicer appears critical for double-stranded RNA cleavage (Du et al. 2008).

MicroRNAs, and by extension endoribonuclease Dicer function, are implicated in virtually every biological process in a wide range of organisms, and changes in their expression are associated with a plethora of human pathologies. In the cerebellum, miRNA dysfunction, via ablation of endoribonuclease Dicer function, has been linked to movement disorders (Lee et al. 2008; Constantin and Wainwright 2015), neurodegeneration (Schaefer et al. 2007), and the malignant neoplasm, medulloblastoma (Zindy et al. 2015). MicroRNAs play a prominent role in medulloblastoma, given that distinct miRNA expression signatures are able to classify the molecular (Cho et al. 2011) and histopathological (Ferretti et al. 2009) subtypes of human medulloblastoma, and dozens of independent studies have identified the functional networks by which specific miRNAs contribute to the growth and progression of this disease. For example, the miR-1792 cluster causally contributes to medulloblastoma and granule cell precursor proliferation through Sonic Hedgehog (Shh)- Patched (Ptch) signaling (Northcott et al. 2009; Uziel et al. 2009). Similarly, miR-106b has been shown to promote the proliferation, migration, and invasion potential of medulloblastoma (Li et al. 2015), presumably via the principal mediator of the transcriptional response of the Shh-Ptch-signaling pathway, GLI-Kruppel family member GLI2 (Gli2) (Constantin and Wainwright 2015).

The cerebellum is located anteriorly on the brainstem, close to the midbrain-hindbrain boundary. It is essential for the fine motor control of movement and posture and, on the basis of human lesion and functional neuroimaging studies, appears to contribute to a broad range of high-order nonmotor functions (see Buckner 2013 for review). A principal cell type of the cerebellum, and the most numerous in the central nervous system, is the granule cell. Granule cells are of critical importance to cerebellar function, as exemplified by the severity of motor coordination, language, and cognitive deficits observed in patients with congenital granule cell degeneration (Pascual-Castroviejo et al. …

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