Essing the basic helix-loop-helix factor Ascl1, whose mutation results in* CorrespondenceEssing the basic helix-loop-helix factor

Essing the basic helix-loop-helix factor Ascl1, whose mutation results in* Correspondence
Essing the basic helix-loop-helix factor Ascl1, whose mutation results in* Correspondence: [email protected]; [email protected] 2 Institut de G ique et de Biologie Mol ulaire et Cellulaire (IGBMC), UMR 7104 CNRS, U 964 INSERM, Universit?de Strasbourg, B.P. 10142, 67404, Illkirch Cedex, France 1 Laboratory for Sensory Development, RIKEN Center for Developmental Biology, Kobe 650-0047, Japana failure of olfactory neurogenesis. Ascl1 is required for induction of the atonal-related gene Neurogenin1 (Neurog1) in immediate neuronal precursors (INPs), which then differentiate into ORNs expressing -III-tubulin [1]. The OE of Ascl1-null mouse mutants contains excessive numbers of precursors expressing Sox2 and Ascl1 [2], indicating that Ascl1 loss-of-function prevents their transition into more differentiated cell types. While the identity of the olfactory stem cell upstream to the Ascl1-expressing progenitor is unclear, a cell type co-expressing Sox2 and Pax6 is a good candidate. These factors are typically associated with multipotent cell types in developing neuroepithelia, and in the OE are expressed in a subset of basal cells that do not express Ascl1 [3]. Acute OE damage by methyl bromide-induced lesion or by olfactory bulbectomy, causes Pax6 upregulation before Ascl1 upregulation [4]. The mechanisms controlling the transition between PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28607003 the different cell states are poorly understood, although computational modeling suggests?2013 Paschaki et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Paschaki et al. Neural Development 2013, 8:13 http://www.neuraldevelopment.com/content/8/1/Page 2 ofthat secreted factors exert exquisite feedback control on different cell populations to ensure a rapid and regulatable response to injury [3]. An interplay between the Tgf ligand GDF11, the activin-binding protein follistatin, and activin/inhibinB, has been described as Nilotinib structure regulating the balance between stem/progenitor cells and INPs, and possibly the choice between neuronal and sustentacular cell fates [5]. Retinoic acid (RA), a metabolite of vitamin A (retinol), is a signaling molecule involved in various developmental processes (refs. [6-8] for reviews). It is synthesized by cell populations expressing one of three retinaldehyde dehydrogenases (RALDH1, 2, 3, whose corresponding genes are also known as Aldh1a1-a3) and, by acting as a ligand for nuclear receptors, stimulates the transcriptional activity of target genes ([9] for a review). Experiments involving murine OE-mesenchymal co-cultures implicated RA as one of the signals involved in OE patterning and/or differentiation [10,11]. However, it is unclear if RA is merely an inductive signal or a neuronal differentiation factor, and/or to what extent RA signaling affects olfactory neurogenesis. Here, we show that retinoid signaling is not required for PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26795252 induction of the OP, but it is a key factor regulating the progression of olfactory neural progenitors into more committed precursors. RA depletion using pharmacological inhibition, or mutation of its synthesizing enzyme RALDH3, results in a failure of progenitor maintenance, and this depletion leads to a diminished capacity of olfactory precursor cells to renew and differentiate into ORNs.Results and disc.