MicroRNA filters Hox temporal transcription noise to confer boundary formation in the spinal cord.
The initial rostrocaudal patterning of the neural tube leads to differential expression of Hox genes that contribute to the specification of motor neuron (MN) subtype identity. Although several 3' Hox mRNAs are expressed in progenitors in a noisy manner, these Hox proteins are not expressed in the progenitors and only become detectable in postmitotic MNs. MicroRNA biogenesis impairment leads to precocious expression and propagates the noise of Hoxa5 at the protein level, resulting in an imprecise Hoxa5-Hoxc8 boundary. Here we uncover, using in silico simulation, two feed-forward Hox-miRNA loops accounting for the precocious and noisy Hoxa5 expression, as well as an ill-defined boundary phenotype in Dicer mutants. Finally, we identify mir-27 as a major regulator coordinating the temporal delay and spatial boundary of Hox protein expression. Our results provide a novel trans Hox-miRNA circuit filtering transcription noise and controlling the timing of protein expression to confer robust individual MN identity.
Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11529, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Chung-Jung
CJ
Li
Center for Complex Biological Systems, Department of Mathematics, University of California, Irvine, California 92697, USA.|Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
Tian
T
Hong
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Ying-Tsen
YT
Tung
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.|Institute of Biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei 10672, Taiwan.
Ya-Ping
YP
Yen
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Ho-Chiang
HC
Hsu
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Ya-Lin
YL
Lu
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Mien
M
Chang
Center for Complex Biological Systems, Department of Mathematics, University of California, Irvine, California 92697, USA.|Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
Qing
Q
Nie
Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11529, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Jun-An
0000-0001-9870-3203
JA
Chen
D000818:Animals; D003198:Computer Simulation; D004622:Embryo, Mammalian / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014158:Transcription, Genetic
D035683:MicroRNAs; D012333:RNA, Messenger; D043244:Ribonuclease III