Diverse functions of microRNAs in nervous system development.
Curr Top Dev Biol. 2012;99:115-43
Authors: Cochella L, Hobert O
MicroRNAs (miRNAs) are integral parts of the gene regulatory networks that control most developmental processes. Through their regulatory action, miRNAs introduce an additional layer of genetic complexity that can translate into increased cellular diversity, something that is extremely relevant to nervous system structure. In addition, miRNAs sharpen the spatial and temporal boundaries between different cellular states during development. Here, we illustrate these roles with a number of specific miRNAs that act during distinct steps of neural development. We further discuss specific aspects of miRNA function that make these regulators particularly suited to provide the robustness and complexity that are essential for the dynamic nature of both the development and activity of the nervous system.
PMID: 22365737 [PubMed - indexed for MEDLINE]
Regulation of terminal differentiation programs in the nervous system.
Annu Rev Cell Dev Biol. 2011;27:681-96
Authors: Hobert O
The generation of individual neuron types in the nervous system is a multistep process whose endpoint is the expression of neuron type-specific batteries of terminal differentiation genes that determine the functional properties of a neuron. This review focuses on the regulatory mechanisms that are involved in controlling the terminally differentiated state of a neuron. I review several case studies from invertebrate and vertebrate nervous systems that reveal that many terminal differentiation features of a neuron are coregulated via terminal selector transcription factors that initiate and maintain terminal differentiation programs.
PMID: 21985672 [PubMed - indexed for MEDLINE]
Transcriptional control of the terminal fate of monoaminergic neurons.
Annu Rev Neurosci. 2011;34:153-84
Authors: Flames N, Hobert O
Monoaminergic neurons are critical functional components of all nervous systems across phylogeny. The terminally differentiated state of individual types of monoaminergic neurons is defined by the coordinated expression of a battery of genes that instructs the synthesis and transport of specific monoamines, such as serotonin or dopamine. Dysfunction or deregulation of several of these enzymes and transporter system has been proposed to be the underlying basis of several pathological conditions. We review here the state of knowledge of the nature of the transcriptional regulatory programs that control the expression of what we term monoaminergic gene batteries (enzymes and transporters for specific monoamines) and thereby define the terminally differentiated state of monoaminergic neurons. We review several case studies in vertebrate and invertebrate model systems and propose that the coordinated expression of the genes that define individual monoaminergic cell types may be brought about by transcriptional coregulatory strategies.
PMID: 21692658 [PubMed - indexed for MEDLINE]
Neurogenesis in the nematode Caenorhabditis elegans.
The nervous system represents the most complex tissue of C. elegans both in terms of numbers (302 neurons and 56 glial cells = 37% of the somatic cells in a hermaphrodite) and diversity (118 morphologically distinct neuron classes). The lineage and morphology of each neuron type has been described in detail and neuronal fate markers exists for virtually all neurons in the form of fluorescent reporter genes. The ability to "phenotype" neurons at high resolution combined with the amenability of C. elegans to genetic mutant analysis make the C. elegans nervous system a prime model system to elucidate the nature of the gene regulatory programs that build a nervous system-a central question of developmental neurobiology. Discussing a number of regulatory genes involved in neuronal lineage determination and neuronal differentiation, I will try to carve out in this review a few general principles of neuronal development in C. elegans. These principles may be conserved across phylogeny.
PMID: 20891032 [PubMed - indexed for MEDLINE]
The molecular and gene regulatory signature of a neuron.
Trends Neurosci. 2010 Oct;33(10):435-45
Authors: Hobert O, Carrera I, Stefanakis N
Neuron-type specific gene batteries define the morphological and functional diversity of cell types in the nervous system. Here, we discuss the composition of neuron-type specific gene batteries and illustrate gene regulatory strategies which determine the unique gene expression profiles and molecular composition of individual neuronal cell types from C. elegans to higher vertebrates. Based on principles learned from prokaryotic gene regulation, we argue that neuronal terminal gene batteries are functionally grouped into parallel-acting 'regulons'. The theoretical concepts discussed here provide testable hypotheses for future experimental analysis of the exact gene-regulatory mechanisms employed in the generation of neuronal diversity and identity.
PMID: 20663572 [PubMed - indexed for MEDLINE]
Lineage programming: navigating through transient regulatory states via binary decisions.
Curr Opin Genet Dev. 2010 Aug;20(4):362-8
Authors: Bertrand V, Hobert O
Lineage-based mechanisms are widely used to generate cell type diversity in both vertebrates and invertebrates. For the past few decades, the nematode Caenorhabditis elegans has served as a primary model system to study this process because of its fixed and well-characterized cell lineage. Recent studies conducted at the level of single cells and individual cis-regulatory elements suggest a general model by which cellular diversity is generated in this organism. During its developmental history a cell passes through multiple transient regulatory states characterized by the expression of specific sets of transcription factors. The transition from one state to another is driven by a general binary decision mechanism acting at each successive division in a reiterative manner and ending up with the activation of the terminal differentiation program upon terminal division. A similar cell fate specification system seems to play a role in generating cellular diversity in the nervous system of more complex organisms such as Drosophila and vertebrates.
PMID: 20537527 [PubMed - indexed for MEDLINE]
Looking beyond development: maintaining nervous system architecture.
Curr Top Dev Biol. 2009;87:175-94
Authors: Bénard C, Hobert O
Neuronal circuitries established in development must persist throughout life. This poses a serious challenge to the structural integrity of an embryonically patterned nervous system as an animal dramatically increases its size postnatally, remodels parts of its anatomy, and incorporates new neurons. In addition, body movements, injury, and ageing generate physical stress on the nervous system. Specific molecular pathways maintain intrinsic properties of neurons in the mature nervous system. Other factors ensure that the overall organization of entire neuronal ensembles into ganglia and fascicles is appropriately maintained upon external challenges. Here, we discuss different molecules underlying these neuronal maintenance mechanisms, with a focus on lessons learned from the nematode Caenorhabditis elegans.
PMID: 19427520 [PubMed - indexed for MEDLINE]
Regulatory logic of neuronal diversity: terminal selector genes and selector motifs.
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20067-71
Individual neuronal cell types are defined by the expression of unique batteries of terminal differentiation genes. The elucidation of the cis-regulatory architecture of several distinct, single neuron type-specific gene batteries in Caenorhabditis elegans has revealed a strikingly simple cis-regulatory logic, in which small cis-regulatory motifs are activated in postmitotic neurons by autoregulating transcription factors (TFs). Loss of the TFs results in the loss of the identity of the individual neuron type. I propose to term these TFs "terminal selector genes" and their cognate cis-regulatory target sites "terminal selector motifs." Terminal selector genes assign individual neuronal identities by directly controlling the expression of downstream, terminal differentiation genes and act in specific regulatory network configurations. The simplicity of the cis-regulatory logic on which the terminal selector gene concept is based may contribute to the evolvability of neuronal diversity.
PMID: 19104055 [PubMed - indexed for MEDLINE]
Gene regulation by transcription factors and microRNAs.
Science. 2008 Mar 28;319(5871):1785-6
The properties of a cell are determined by the genetic information encoded in its genome. Understanding how such information is differentially and dynamically retrieved to define distinct cell types and cellular states is a major challenge facing molecular biology. Gene regulatory factors that control the expression of genomic information come in a variety of flavors, with transcription factors and microRNAs representing the most numerous gene regulatory factors in multicellular genomes. Here, I review common principles of transcription factor- and microRNA-mediated gene regulatory events and discuss conceptual differences in how these factors control gene expression.
PMID: 18369135 [PubMed - indexed for MEDLINE]
Reporter gene fusions.
Authors: Boulin T, Etchberger JF, Hobert O
PMID: 18050449 [PubMed - indexed for MEDLINE]
Specification of the nervous system.
Nervous systems are characterized by an astounding degree of cellular diversity. The nematode Caenorhabditis elegans has served as a valuable model system to define the genetic programs that serve to generate cellular diversity in the nervous system. This review discusses neuronal diversity in C. elegans and provides an overview of the molecular mechanisms that define and specify neuronal cell types in C. elegans.
PMID: 18050401 [PubMed - indexed for MEDLINE]
The molecular diversity of glycosaminoglycans shapes animal development.
Annu Rev Cell Dev Biol. 2006;22:375-407
Authors: Bülow HE, Hobert O
Proteoglycans (PGs), molecules in which glycosaminoglycans (GAGs) are covalently linked to a protein core, are components of the extracellular matrix of all multicellular organisms. Sugar moieties in GAGs are often extensively modified, which make these molecules enormously complex. We discuss here the role of PGs during animal development, emphasizing the in vivo significance of sugar modifications. We explore a model in which the modification patterns of GAG chains may provide a specific code that contributes to the correct development of a multicellular organism.
PMID: 16805665 [PubMed - indexed for MEDLINE]
Uses of GFP in Caenorhabditis elegans.
Methods Biochem Anal. 2006;47:203-26
Authors: Hobert O, Loria P
PMID: 16335715 [PubMed - indexed for MEDLINE]
MicroRNAs: all gone and then what?
Curr Biol. 2005 May 24;15(10):R387-9
MicroRNAs are abundant gene regulatory factors whose function in animal development and homeostasis is poorly understood. A new study reports the genetic elimination of miRNA function on a full genomic scale and identifies a subfamily of miRNAs involved in brain morphogenesis.
PMID: 15916942 [PubMed - indexed for MEDLINE]
Common logic of transcription factor and microRNA action.
Trends Biochem Sci. 2004 Sep;29(9):462-8
Over the past few years, microRNAs (miRNAs) have emerged as abundant regulators of gene expression. Like many transcription factors (TFs), miRNAs are important determinants of cellular fate specification. Here I provide a conceptual framework for miRNA action in the context of creating cellular diversity in a developing organism, and emphasize the conceptual similarity of TF- and miRNA-mediated control of gene expression. Both TFs and miRNAs are trans-acting factors that exert their activity through composite cis-regulatory elements that are 'hard-wired' into DNA or RNA. TFs and miRNAs act in a largely combinatorial manner - that is, many different TFs or miRNAs control one gene - and they act cooperatively on their targets - that is, there are several cis-regulatory elements for a single TF or miRNA species in a target gene. Just as the set of TFs in a given cell type has been proposed to constitute a 'code' that specifies cellular differentiation, so 'miRNA codes' are likely to have conceptually similar roles in the specification of cell types.
PMID: 15337119 [PubMed - indexed for MEDLINE]
New insights into the diversity and function of neuronal immunoglobulin superfamily molecules.
Annu Rev Neurosci. 2003;26:207-38
Authors: Rougon G, Hobert O
Immunoglobulin superfamily (IgSF) proteins are implicated in diverse steps of brain development, including neuronal migration, axon pathfinding, target recognition and synapse formation, as well as in the maintenance and function of neuronal networks in the adult. We provide here a review of recent findings on the diversity and the role of transmembrane and secreted members of IgSF proteins in the nervous system. We illustrate that the complexity of IgSF protein function results from various different levels of regulation including regulation of gene expression, protein localization, and protein interactions.
PMID: 12598678 [PubMed - indexed for MEDLINE]
Development and maintenance of neuronal architecture at the ventral midline of C. elegans.
Curr Opin Neurobiol. 2003 Feb;13(1):70-8
Authors: Hobert O, Bülow H
Work in flies, nematodes and vertebrates has shown that genes involved in axon patterning at the ventral midline are functionally conserved across phylogeny. Recent studies in Caenorhabditis elegans have implicated several new extracellular molecules, such as nidogen and heparan sulfate proteoglycans, in axonal tract formation at the midline. Furthermore, a conceptually new mechanism that regulates the maintenance of axon positioning at the midline has been described in C. elegans.
PMID: 12593984 [PubMed - indexed for MEDLINE]
Behavioral plasticity in C. elegans: paradigms, circuits, genes.
J Neurobiol. 2003 Jan;54(1):203-23
Life in the soil is an intellectual and practical challenge that the nematode Caenorhabditis elegans masters by utilizing 302 neurons. The nervous system assembled by these 302 neurons is capable of executing a variety of behaviors, some of respectable complexity. The simplicity of the nervous system, its thoroughly characterized structure, several sets of well-defined behaviors, and its genetic amenability combined with its isogenic background make C. elegans an attractive model organism to study the genetics of behavior. This review describes several behavioral plasticity paradigms in C. elegans and their underlying neuronal circuits and then goes on to review the forward genetic analysis that has been undertaken to identify genes involved in the execution of these behaviors. Lastly, the review outlines how reverse genetics and genomic approaches can guide the analysis of the role of genes in behavior and why and how they will complement the forward genetic analysis of behavior.
PMID: 12486705 [PubMed - indexed for MEDLINE]