The Dlx5 and Foxg1 transcription factors, linked via miRNA-9 and -200, are required for the development of the olfactory and GnRH system.

Abstract

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.

• Authors: Giulia Garaffo, Daniele Conte, Paolo Provero, Daniela Tomaiuolo, Zheng Luo, Patrizia Pinciroli, Clelia Peano, Ilaria D'Atri, Yorick Gitton, Talya Etzion, Yoav Gothilf, Dafne Gays, Massimo M Santoro, Giorgio R Merlo
• Journal: Molecular and cellular neurosciences (Mol Cell Neurosci) Vol. 68 Pg. 103-19 (Sep 2015) ISSN: 1095-9327 [Electronic] United States
• PMID: 25937343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Dlx5 protein, mouse
• Forkhead Transcription Factors
• Foxg1 protein, mouse
• Homeodomain Proteins
• Luminescent Proteins
• MicroRNAs
• Nerve Tissue Proteins
• Gonadotropin-Releasing Hormone

Topics

• Animals
• Animals, Genetically Modified
• Cell Differentiation (genetics)
• Cells, Cultured
• Embryo, Mammalian
• Female
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation, Developmental (genetics)
• Gonadotropin-Releasing Hormone (genetics, metabolism)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Luminescent Proteins (genetics, metabolism)
• Mice
• MicroRNAs (metabolism)
• Mutation (genetics)
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (physiology)
• Olfactory Mucosa (cytology, embryology)
• Olfactory Pathways (cytology, physiology)
• Pregnancy
• Zebrafish