MicroRNA miR-9 Modifies Motor Neuron Columns by a Tuning Regulation of FoxP1 Levels in Developing Spinal Cords

Abstract

The precise organization of motor neuron subtypes in a columnar pattern in developing spinal cords is controlled by cross-interactions of multiple transcription factors and segmental expressions of Hox genes and their accessory proteins. Accurate expression levels and domains of these regulators are essential for organizing spinal motor neuron columns and axonal projections to target muscles. Here, we show that microRNA miR-9 is transiently expressed in a motor neuron subtype and displays overlapping expression with its target gene FoxP1. Overexpression or knockdown of miR-9 alters motor neuron subtypes, switches columnar identities, and changes axonal innervations in developing chick spinal cords. miR-9 modifies spinal columnar organization by specifically regulating FoxP1 protein levels, which in turn determine distinct motor neuron subtypes. Our findings demonstrate that miR-9 is an essential regulator of motor neuron specification and columnar formation. Moreover, the overlapping expression of miR-9 and its target FoxP1 further illuminates the importance of fine-tuning regulation by microRNAs in motor neuron development.

MicroRNA-9

“…3G and H). 23,24 In mice, miR-9 is readily detected in the forebrain and hindbrain starting on embryonic day (E) 9.5. 25 Initially, miR-9 identical to those in vertebrates (named as miR-9a), 22 also possess miR-9 copies that differ in their mature sequence from human miR-9.…”

“…12,13 In the chick, miR-9 is transiently expressed in a pool of spinal motor neurons. 24 Xenopus miR-9 seems to be confined to neural progenitor cells (NPCs) in both the forebrain and hindbrain but is expressed only in differentiated forebrain neurons. …”

“…24 While miR-9 plays a central role in the differentiation of motor neuron subtypes, it does not seem to affect overall neurogenesis, as the number of NPCs and differentiated neurons remains normal, 24 which is in stark contrast to its roles in the brains of several model organisms.…”

Noncoding RNAs in Neural Stem Cell Development

“…In zebrafish, miR-9 promotes differentiation of NPs that give rise to neurons at the midbrain-hindbrain domain and controls the organization of the midbrain-hindbrain boundary by targeting several genes in the Fibroblast growth factor (Fgf) signaling, such as fgf8-1 and fgfr1 (Leucht et al, 2008). In the chick spinal cord, miR-9 specifies a subtype of motor neurons that project axons to the axial muscles from motor neuron progenitors by specifically targeting transcription factor FoxP1 (Otaegi et al, 2011).…”

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers

“…Intensive studies have been carried out investigating the involvement of miRs in human malignant tumors due to their ability to regulate several genes involved in multiple cancer pathways (5). miRs are highly involved in various cell processes, including proliferation, differentiation, apoptosis and development, by simultaneously controlling the expression levels of hundreds of genes (6,7). In cancer cells, both oncogenic and tumor suppressive miRs have been reported to contribute to cancer development and progression (7,8).…”