miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

Abstract

The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation.

Retracted:MicroRNA‐219 decreases hippocampal long‐term potentiation inhibition and hippocampal neuronal cell apoptosis in type 2 diabetes mellitus mice by suppressing theNMDARsignaling pathway

“…Its downregulation is significant as it leads to the downregulation of the genes in RNA processing . In addition, the downregulation of miR‐219 is consistent with a single brief re‐exposure to the context that could inhibit the signaling activity and promote memory reconsolidation . It has been reported that miR‐219 participates in the NMDAR signaling by regulating the expression of pathway genes .…”

The presence or absence alone of miRNA isoforms (isomiRs) successfully discriminate amongst the 32 TCGA cancer types

“…Another miRNA that also exhibited similar characteristics in LGG was miR-219 and, intriguingly, this miRNA has been implicated in neural differentiation processes (52). We were also able to identify additional miRNAs that have almost unique expression in some tissues, like the liver-specific arms of miR-122 (53).…”

Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR‐219a‐5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1

“…A recent study suggested that overexpression of miR‐219 in neural stem cells robustly inhibits cell proliferation and induces neuronal differentiation (Murai et al ). Another recent report also described that miR‐219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving neural progenitors towards differentiation (Hudish et al ). Recently, miR‐219a‐5p was reported to play a crucial role in schizophrenia, osteosarcoma, and age‐related bone loss (Hass et al ; Li et al ; Aquino‐Martinez et al ).…”