Project description:Neural basic helix-loop-helix (bHLH) transcription factors are important for the differentiation and cell type specification of neurons. They are thought to share direct downstream targets in their common role as neuronal differentiation factors, but have distinct targets with respect to their cell type specific roles. Little is known about distinct cell-type specific bHLH targets as previous work did not distinguish these from common targets. Based on previous genetic evidence, we hypothesize that bHLH transcription factors have unique targets for their function in regulating neuronal sub-type specification. Atoh1 (Math1) is a bHLH transcription factor that specifies different cell types of the proprioceptive pathway in mammals such as the dorsal interneuron 1 population of the developing neural tube. Using microarray analyses of neighboring specific bHLH sorted populations from developing mouse neural tubes, we determine transcripts unique to the Atoh1-derived population and not those common to bHLH transcription factors in related neural progenitor populations. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments of native tissue followed by enhancer reporter analyses identified five direct cell-type specific targets of Atoh1 in vivo: Klf7, Rab15, Rassf4, Selm, and Smad7, along with their Atoh1-responsive enhancers. These Atoh1 targets were found from native tissue in the appropriate developmental context and have diverse functions that range from transcription factors to regulators of endocytosis and signaling pathways. Only Rab15 and Selm are expressed across several different Atoh1-specified cell types including external granule cells (EGL) in the developing cerebellum, hair cells of the inner ear, and Merkel cells, demonstrating that even within Atoh1 lineages, not all Atoh1 specific targets are shared. Our work establishes on a molecular level that the neuronal differentiation bHLH transcription factors also have distinct targets for their roles in neuronal sub-type specification. From this work, we can begin to address how bHLH transcription factors are able to specify unique cell types and initiate programs that organize neuronal diversity.

Project description:Muraro2014 - Vascular patterning in Arabidopsis roots Using a multicellular model, maintanence of vascular patterning in Arabidopsis roots has been studied. The model that is provided here is the single-cell version of the model. The two-cell and multicellular models described in the paper can be downloaded as python scripts (follow the curation tab to get these files). This model is described in the article: Integration of hormonal signaling networks and mobile microRNAs is required for vascular patterning in Arabidopsis roots. Muraro D, Mellor N, Pound MP, Help H, Lucas M, Chopard J, Byrne HM, Godin C, Hodgman TC, King JR, Pridmore TP, Helariutta Y, Bennett MJ, Bishopp A. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):857-62. Abstract: As multicellular organisms grow, positional information is continually needed to regulate the pattern in which cells are arranged. In the Arabidopsis root, most cell types are organized in a radially symmetric pattern; however, a symmetry-breaking event generates bisymmetric auxin and cytokinin signaling domains in the stele. Bidirectional cross-talk between the stele and the surrounding tissues involving a mobile transcription factor, SHORT ROOT (SHR), and mobile microRNA species also determines vascular pattern, but it is currently unclear how these signals integrate. We use a multicellular model to determine a minimal set of components necessary for maintaining a stable vascular pattern. Simulations perturbing the signaling network show that, in addition to the mutually inhibitory interaction between auxin and cytokinin, signaling through SHR, microRNA165/6, and PHABULOSA is required to maintain a stable bisymmetric pattern. We have verified this prediction by observing loss of bisymmetry in shr mutants. The model reveals the importance of several features of the network, namely the mutual degradation of microRNA165/6 and PHABULOSA and the existence of an additional negative regulator of cytokinin signaling. These components form a plausible mechanism capable of patterning vascular tissues in the absence of positional inputs provided by the transport of hormones from the shoot. This model is hosted on BioModels Database and identified by: BIOMD0000000522 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Neural basic helix-loop-helix (bHLH) transcription factors are important for the differentiation and cell type specification of neurons. They are thought to share direct downstream targets in their common role as neuronal differentiation factors, but have distinct targets with respect to their cell type specific roles. Little is known about distinct cell-type specific bHLH targets as previous work did not distinguish these from common targets. Based on previous genetic evidence, we hypothesize that bHLH transcription factors have unique targets for their function in regulating neuronal sub-type specification. Atoh1 (Math1) is a bHLH transcription factor that specifies different cell types of the proprioceptive pathway in mammals such as the dorsal interneuron 1 population of the developing neural tube. Using microarray analyses of neighboring specific bHLH sorted populations from developing mouse neural tubes, we determine transcripts unique to the Atoh1-derived population and not those common to bHLH transcription factors in related neural progenitor populations. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments of native tissue followed by enhancer reporter analyses identified five direct cell-type specific targets of Atoh1 in vivo: Klf7, Rab15, Rassf4, Selm, and Smad7, along with their Atoh1-responsive enhancers. These Atoh1 targets were found from native tissue in the appropriate developmental context and have diverse functions that range from transcription factors to regulators of endocytosis and signaling pathways. Only Rab15 and Selm are expressed across several different Atoh1-specified cell types including external granule cells (EGL) in the developing cerebellum, hair cells of the inner ear, and Merkel cells, demonstrating that even within Atoh1 lineages, not all Atoh1 specific targets are shared. Our work establishes on a molecular level that the neuronal differentiation bHLH transcription factors also have distinct targets for their roles in neuronal sub-type specification. From this work, we can begin to address how bHLH transcription factors are able to specify unique cell types and initiate programs that organize neuronal diversity. Gene expression analysis: Two samples, Atoh1-GFP and dNeurog1-GFP, were analyzed. Two biological replicates of each. Atoh1-GFP transgenics are mice with GFP inserted into a BAC that drives GFP to the Atoh1-derived population of the developing neural tube marking the dorsal interneuron 1 population (Raft et al. Development 2007). dNeurog1-GFP transgenics are mice with a Neurog1 enhancer that drives GFP to the dorsal part of the developing neural tube marking the dorsal interneuron 2 population (Nakada et al. Dev Bio 2004). Chip-seq analysis: Series GSE22111

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