The Dlx5 and Foxg1 transcription factors, linked via miRNA-9 and -200, are required for the development of the olfactory and GnRH system.
During neuronal development and maturation, microRNAs (miRs) play diverse functions ranging from early patterning, proliferation and commitment to differentiation, survival, homeostasis, activity and plasticity of more mature and adult neurons. The role of miRs in the differentiation of olfactory receptor neurons (ORNs) is emerging from the conditional inactivation of Dicer in immature ORN, and the depletion of all mature miRs in this system. Here, we identify specific miRs involved in olfactory development, by focusing on mice null for Dlx5, a homeogene essential for both ORN differentiation and axon guidance and connectivity. Analysis of miR expression in Dlx5(-/-) olfactory epithelium pointed to reduced levels of miR-9, miR-376a and four miRs of the -200 class in the absence of Dlx5. To functionally examine the role of these miRs, we depleted miR-9 and miR-200 class in reporter zebrafish embryos and observed delayed ORN differentiation, altered axonal trajectory/targeting, and altered genesis and position of olfactory-associated GnRH neurons, i.e. a phenotype known as Kallmann syndrome in humans. miR-9 and miR-200-class negatively control Foxg1 mRNA, a fork-head transcription factor essential for development of the olfactory epithelium and of the forebrain, known to maintain progenitors in a stem state. Increased levels of z-foxg1 mRNA resulted in delayed ORN differentiation and altered axon trajectory, in zebrafish embryos. This work describes for the first time the role of specific miR (-9 and -200) in olfactory/GnRH development, and uncovers a Dlx5-Foxg1 regulation whose alteration affects receptor neuron differentiation, axonal targeting, GnRH neuron development, the hallmarks of the Kallmann syndrome.
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Giulia
G
Garaffo
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Daniele
D
Conte
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Paolo
P
Provero
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Daniela
D
Tomaiuolo
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Zheng
Z
Luo
Doctorate School in Molecular Medicine, Dept. Medical Biotechnology Translational Medicine (BIOMETRA), University of Milano, Italy.
Patrizia
P
Pinciroli
Inst. of Biomedical Technology, National Research Council, ITB-CNR Segrate (MI) Italy.
Clelia
C
Peano
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Ilaria
I
D'Atri
UMR7221 CNRS/MNHN - Evolution des régulations endocriniennes - Paris, France.
Yorick
Y
Gitton
Dept. Neurobiology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; VIB, Vesalius Research Center, KU Leuven, Belgium.
Talya
T
Etzion
Dept. Neurobiology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; VIB, Vesalius Research Center, KU Leuven, Belgium.
Yoav
Y
Gothilf
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy.
Dafne
D
Gays
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy; Dept. Neurobiology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; VIB, Vesalius Research Center, KU Leuven, Belgium.
Massimo M
MM
Santoro
Dept. Molecular Biotechnology and Health Sciences, University of Torino, Italy. Electronic address: giorgioroberto.merlo@unito.it.
Giorgio R
GR
Merlo
D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D009831:Olfactory Mucosa / Q000166:cytology / Q000196:embryology; D009833:Olfactory Pathways / Q000166:cytology / Q000502:physiology*; D011247:Pregnancy; D015027:Zebrafish
C501120:Dlx5 protein, mouse; D051858:Forkhead Transcription Factors; C489565:Foxg1 protein, mouse; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D007987:Gonadotropin-Releasing Hormone
Dlx; Foxg1; GnRH; Kallmann syndrome; Neuronal differentiation; Olfactory development; microRNA