HomeDate: 2017-04-12
Dr. Jun-An Chen, an Assistant Research Fellow from IMB, Academia Sinica, who collaborated with Prof. Qing Nie from the Mathematics Department of UC Irvine, uncovered a novel microRNA (miRNA) - Hox gene expression network that contributes to the dynamic control of Hox gene expression and proper motor neuron (MN) subtype identities during development. This model was established with in silico mathematical simulations and further examined by embryonic stem cell differentiation systems and mouse and chicken embryos. Their work was published in the Nature Communications on Mar 24, 2017, and the title is “MicroRNA Filters Hox Temporal Transcription Noise to Confer Boundary Formation in the Spinal Cord”.
Hox genes have been extensively studied for more than 30 years. Although it is well-known that Hox genes are essential to the specification of spinal MN subtype identities along the rostrocaudal axis, it remains unclear how the Hox genes are precisely regulated to achieve their collinear spatiotemporal expression. During MN development, Hox genes are expressed in a specific distribution with regard to time and space during spinal cord development. The specific pattern of Hox gene expression then contributes to the specification of MN subtype identity, which in turn affects the innervation pattern of their respective muscle targets. Previous studies have reported a delay of Hox proteins translation from mRNA—while the mRNAs of Hox genes are detected in progenitor stage, Hox proteins are not translated until in postmitotic MNs.
MiRNAs belong to a class of non-coding RNAs (ncRNAs) that regulate cell function by repressing the translation of target mRNAs post-transcriptionally. The Chen laboratory hypothesized that miRNA might mediate the delay of Hox protein translation. Indeed, when MN progenitor cells lose miRNA biogenesis upon Dicer deletion, they start to translate Hoxa5 mRNAs into proteins, instead of holding the translation until becoming postmitotic MNs. Such precocious expression of Hoxa5 protein results in noisy distribution of Hoxa5 proteins in the progenitor MN domain and further leads to the disruption of Hox5-Hox8 boundary of postmitotic MNs, which is essential for defining MN subtype identities. Dr. Chen’s team then explored the topology of Hox gene and miRNA network in silico and identified two feed-forward Hox-miRNA loops accounting for the observed phenotypes. Finally, they identified a specific miRNA, mir-27, as a major regulator for the temporal delay and spatial collinearity of Hox protein expression via gain- and loss-of-function studies in vitro and in vivo. It is noted that the mir-27 dependent phenotype can be recapitulated in chicken embryos, indicating this novel Hox-miRNA genetic circuit is essential and well preserved during evolution.
The primary authors of the article are Chung-Jung Li, a TIGP student in Academia Sinica, and Dr. Tian Hong from UCI. This study is supported by Academia Sinica, MOST and NHRI.
