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Marco Milán - One of the best experts on this subject based on the ideXlab platform.
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PERSPECTIVE Gene-Regulatory Logic to Induce and Maintain a Developmental Compartment
2016Co-Authors: Marco MilánAbstract:Forty-four years ago, Antonio García-Bellido utilized, for the first time in biology, the clonal anal-ysis technique to characterize the parameters of proliferation and growth of a developing organ —in this case, the highly proliferative wing primordium ofDrosophila [1]. A couple of years later, using the same technique, García-Bellido and two of his PhD students, Ginés Morata and Pedro Ripoll, reported the existence of adjacent cell populations that do not mix, which he called Compartments [2]. Developmental Compartmentalization of growing organs was subsequently demonstrated in all ectodermal derivatives of the fruit fly, as well as in vertebrate limbs and in the central nervous system. One of the most remarkable features of Compartments is that their boundaries also act as organizing centers. Compartments are defined by the restricted expression and activity of the so-called selector genes. The homeodomain-encoding gene engrailed was rap-idly identified as the one specifying the posterior Compartment of all ectodermal derivatives of the fruit fly [3,4]. It was not until the early 1990s that the LIM-homeodomain-encoding gene apterous (ap) was shown to specify the dorsal Compartment in theDrosophila wing [5]. These selector genes share three distinct activities: specification of Compartment identity, localization of an organizing center at the Compartment boundary, and establishment of the lineage restrictio
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gene regulatory logic to induce and maintain a Developmental Compartment
PLOS Genetics, 2015Co-Authors: Marco MilánAbstract:Forty-four years ago, Antonio Garcia-Bellido utilized, for the first time in biology, the clonal analysis technique to characterize the parameters of proliferation and growth of a developing organ—in this case, the highly proliferative wing primordium of Drosophila [1]. A couple of years later, using the same technique, Garcia-Bellido and two of his PhD students, Gines Morata and Pedro Ripoll, reported the existence of adjacent cell populations that do not mix, which he called Compartments [2]. Developmental Compartmentalization of growing organs was subsequently demonstrated in all ectodermal derivatives of the fruit fly, as well as in vertebrate limbs and in the central nervous system. One of the most remarkable features of Compartments is that their boundaries also act as organizing centers. Compartments are defined by the restricted expression and activity of the so-called selector genes. The homeodomain-encoding gene engrailed was rapidly identified as the one specifying the posterior Compartment of all ectodermal derivatives of the fruit fly [3,4]. It was not until the early 1990s that the LIM-homeodomain-encoding gene apterous (ap) was shown to specify the dorsal Compartment in the Drosophila wing [5]. These selector genes share three distinct activities: specification of Compartment identity, localization of an organizing center at the Compartment boundary, and establishment of the lineage restriction border. The ap selector gene rapidly became a paradigm in the identification of the signaling molecules, cell adhesion proteins, and transcription factors that mediate the construction of Compartments and organizing centers [6–9]. However, how ap expression is maintained in order to fulfill its functions in all the cells of the dorsal Compartment during the five days of growth and proliferation has remained largely unknown. In this issue of PLOS Genetics, Carlos Estella and colleagues [10] unravel the molecular mechanisms underlying the initiation and maintenance of ap expression in the Drosophila wing primordium. A combination of enhancers, autoregulatory and feed-forward mechanisms, and epigenetics appears to be at play. Perhaps the best way of identifying the noncoding regions involved in the regulation of expression of a gene of interest is through classical genetics and phenotypic characterization. Indeed, this is the approach taken by Estella and colleagues in their analysis of the ap locus. A series of endogenous deletions were performed to identify the regulatory sequences required to drive ap expression and give rise to normal-looking adult wings. By doing so, the authors functionally identified a proximal region harboring a Polycomb Response Element (PRE) and a distal fragment containing a previously identified enhancer, whose deletions severely compromised ap expression and wing development. The authors next undertook a systematic in situ dissection of the ap cis-regulatory domain by bringing back sub-fragments of a previously deleted region and analyzing their capacity to rescue the wing phenotype. When combined, the PRE and two enhancers located in a distal fragment were sufficient to rescue both ap expression and wing formation. So far so good, but what is the regulatory logic that combines the input of two distinct enhancers and a PRE to induce the expression and maintenance of ap expression in all dorsal cells throughout development? The authors again approached this issue in a clever manner. They constructed a battery of lacZ reporter lines to decipher how these enhancers were expressed in the wing, to identify the transcription factor involved in their regulation, and to analyze the contribution of the PRE to this process. As expected, the two functional enhancers located in a distal fragment and identified by the in situ rescue experiment drove expression of the lacZ reporter in dorsal cells of the wing primordium. The isolated ap-E enhancer is initially expressed in all dorsal cells and responds to the early activity of the Epidermal Growth Factor (EGF)-Receptor ligand Vein, as does the whole ap locus [11]. Interestingly, its initial expression coincides in time with the onset of ap expression and the initiation of the organizing activities of the Compartment boundary through the activation of the Notch receptor. Later in development, expression of the ap-E enhancer fades away from the dorsal Compartment of the wing primordium, and the ap-DV enhancer starts to be expressed in exactly the same region as a consequence of the activity of the Apterous and Vestigial proteins. It is interesting to note that Vestigial is a target of Notch [12]. Thus, both an Apterous-dependent autoregulatory mechanism and a feed-forward mechanism, through the activity of Notch and Vestigial, drive the expression of the ap-DV enhancer. The authors observed that these two enhancers were not able—either alone or in combination—to completely reproduce the ap expression pattern. Thus, additional elements appear to be at work. Following the logic of the in situ rescue experiments, the combination of the ap-E and ap-DV enhancers, together with the ap-PRE, gave rise to robust expression of the lacZ reporter in all dorsal cells throughout wing development. Interestingly, the ability of the ap-PRE to drive robust expression was shown to rely on the activity of the Trithorax group of proteins. Taken together, the results from Estella and colleagues reveal a three-step molecular mechanism to initiate and maintain ap expression in all dorsal cells throughout development (Fig 1). Whereas the onset of ap expression relies on the restricted expression of the EGF receptor ligand Vein and on the activity of the EGF-Receptor responsive transcription factor Pointed-P1 in the presumptive dorsal Compartment, the maintenance of ap expression during the subsequent stages of wing development is led by an Apterous-dependent autoregulatory loop, a Vestigial-mediated feed-forward mechanism, and the activity of the PRE. This initiation and maintenance mechanism has remarkable commonalities with the logic followed by other Developmental genes whose expression has to be precisely initiated but also robustly maintained throughout the dramatic increase in tissue size and cell number that occurs in the primordia of the adult fly [13,14]. Forty-two years after the discovery of Compartments, the Drosophila wing is still unraveling common principles of development. Fig 1 Illustration of the apterous locus with its regulatory regions involved in the control of its expression in the Drosophila wing.
Leonard M Eisenman - One of the best experts on this subject based on the ideXlab platform.
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further evidence for a unique Developmental Compartment in the cerebellum of the meander tail mutant mouse as revealed by the quantitative analysis of purkinje cells
The Journal of Comparative Neurology, 1996Co-Authors: Julie A Napieralski, Leonard M EisenmanAbstract:The cerebellum of the meander tail mutant mouse (mea/mea) is characterized by a relatively normal cytoarchitecture posteriorly with an abrupt transition to an anterior region in which there is abnormal foliation, agranularity, and Purkinje cell (PC) ectopia. This study presents the results of a qualitative and quantitative analysis of the PC in the mea/mea cerebellum. Developmental and morphological analyses reveal that the PC in the anterior region of the mea/mea cerebellum do not form a monolayer during the first week of postnatal development as they do in the wild type mouse. In the adult mea/mea, the dendrites of these ectopic cells are atrophic and disoriented. Quantitative studies in adult animals reveal that while the total number of PC is normal, the number of PC in the affected anterior region of the mea/mea cerebellum is greater than the number of PC in the anterior lobe, as classically defined by the primary fissure, of the normal animal. These data suggest that 1) the Developmental morphology of the PC in the anterior region is abnormal, probably due to the lack of granule cells at early postnatal times; 2) the total number of PC in the cerebellum is normal, and 3) the defect is not restricted to the anterior lobe but involves a portion of the posterior lobe. The latter supports the notion that the mutant gene affects a unique Developmental Compartment in the cerebellum which does not coincide with the classic adult boundary, the primary fissure, between the anterior and posterior lobes.
Carlos Estella - One of the best experts on this subject based on the ideXlab platform.
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Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules
PLoS genetics, 2015Co-Authors: Dimitri Bieli, Oguz Kanca, David Requena, Fisun Hamaratoglu, Daryl M. Gohl, Paul Schedl, Markus Affolter, Matthew Slattery, Martin Müller, Carlos EstellaAbstract:The subdivision of cell populations in Compartments is a key event during animal development. In Drosophila, the gene apterous (ap) divides the wing imaginal disc in dorsal vs ventral cell lineages and is required for wing formation. ap function as a dorsal selector gene has been extensively studied. However, the regulation of its expression during wing development is poorly understood. In this study, we analyzed ap transcriptional regulation at the endogenous locus and identified three cis-regulatory modules (CRMs) essential for wing development. Only when the three CRMs are combined, robust ap expression is obtained. In addition, we genetically and molecularly analyzed the trans-factors that regulate these CRMs. Our results propose a three-step mechanism for the cell lineage Compartment expression of ap that includes initial activation, positive autoregulation and Trithorax-mediated maintenance through separable CRMs.
Julie A Napieralski - One of the best experts on this subject based on the ideXlab platform.
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further evidence for a unique Developmental Compartment in the cerebellum of the meander tail mutant mouse as revealed by the quantitative analysis of purkinje cells
The Journal of Comparative Neurology, 1996Co-Authors: Julie A Napieralski, Leonard M EisenmanAbstract:The cerebellum of the meander tail mutant mouse (mea/mea) is characterized by a relatively normal cytoarchitecture posteriorly with an abrupt transition to an anterior region in which there is abnormal foliation, agranularity, and Purkinje cell (PC) ectopia. This study presents the results of a qualitative and quantitative analysis of the PC in the mea/mea cerebellum. Developmental and morphological analyses reveal that the PC in the anterior region of the mea/mea cerebellum do not form a monolayer during the first week of postnatal development as they do in the wild type mouse. In the adult mea/mea, the dendrites of these ectopic cells are atrophic and disoriented. Quantitative studies in adult animals reveal that while the total number of PC is normal, the number of PC in the affected anterior region of the mea/mea cerebellum is greater than the number of PC in the anterior lobe, as classically defined by the primary fissure, of the normal animal. These data suggest that 1) the Developmental morphology of the PC in the anterior region is abnormal, probably due to the lack of granule cells at early postnatal times; 2) the total number of PC in the cerebellum is normal, and 3) the defect is not restricted to the anterior lobe but involves a portion of the posterior lobe. The latter supports the notion that the mutant gene affects a unique Developmental Compartment in the cerebellum which does not coincide with the classic adult boundary, the primary fissure, between the anterior and posterior lobes.
Dimitri Bieli - One of the best experts on this subject based on the ideXlab platform.
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Establishment of a Developmental Compartment Requires Interactions between Three Synergistic Cis-regulatory Modules
PLoS genetics, 2015Co-Authors: Dimitri Bieli, Oguz Kanca, David Requena, Fisun Hamaratoglu, Daryl M. Gohl, Paul Schedl, Markus Affolter, Matthew Slattery, Martin Müller, Carlos EstellaAbstract:The subdivision of cell populations in Compartments is a key event during animal development. In Drosophila, the gene apterous (ap) divides the wing imaginal disc in dorsal vs ventral cell lineages and is required for wing formation. ap function as a dorsal selector gene has been extensively studied. However, the regulation of its expression during wing development is poorly understood. In this study, we analyzed ap transcriptional regulation at the endogenous locus and identified three cis-regulatory modules (CRMs) essential for wing development. Only when the three CRMs are combined, robust ap expression is obtained. In addition, we genetically and molecularly analyzed the trans-factors that regulate these CRMs. Our results propose a three-step mechanism for the cell lineage Compartment expression of ap that includes initial activation, positive autoregulation and Trithorax-mediated maintenance through separable CRMs.