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Article ; Online: Axon pathfinding for locomotion.

Bonanomi, Dario

Seminars in cell & developmental biology

2017 Volume 85, Page(s) 26–35

Abstract: Motor neurons of the spinal cord are responsible for the assembly of neuromuscular connections indispensable for basic locomotion and skilled movements. A precise spatial relationship exists between the position of motor neuron cell bodies in the spinal ... ...

Abstract	Motor neurons of the spinal cord are responsible for the assembly of neuromuscular connections indispensable for basic locomotion and skilled movements. A precise spatial relationship exists between the position of motor neuron cell bodies in the spinal cord and the course of their axonal projections to peripheral muscle targets. Motor neuron innervation of the vertebrate limb is a prime example of this topographic organization and by virtue of its accessibility and predictability has provided access to fundamental principles of motor system development and neuronal guidance. The seemingly basic binary map established by genetically defined motor neuron subtypes that target muscles in the limb is directed by a surprisingly large number of directional cues. Rather than being simply redundant, these converging signaling pathways are hierarchically linked and cooperate to increase the fidelity of axon pathfinding decisions. A current priority is to determine how multiple guidance signals are integrated by individual growth cones and how they synergize to delineate class-specific axonal trajectories.
MeSH term(s)	Animals ; Axon Guidance ; Axons/metabolism ; Humans ; Locomotion ; Motor Neurons/metabolism
Language	English
Publishing date	2017-11-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2017.11.014
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Article ; Online: Depletion of Mettl3 in cholinergic neurons causes adult-onset neuromuscular degeneration.

Dermentzaki, Georgia / Furlan, Mattia / Tanaka, Iris / Leonardi, Tommaso / Rinchetti, Paola / Passos, Patricia M S / Bastos, Alliny / Ayala, Yuna M / Hanna, Jacob H / Przedborski, Serge / Bonanomi, Dario / Pelizzola, Mattia / Lotti, Francesco

Cell reports

2024 Volume 43, Issue 4, Page(s) 113999

Abstract: Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN ... ...

Abstract	Motor neuron (MN) demise is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Post-transcriptional gene regulation can control RNA's fate, and defects in RNA processing are critical determinants of MN degeneration. N
MeSH term(s)	Animals ; Methyltransferases/metabolism ; Methyltransferases/genetics ; Mice ; Cholinergic Neurons/metabolism ; Cholinergic Neurons/pathology ; DNA-Binding Proteins/metabolism ; DNA-Binding Proteins/genetics ; Humans ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Adenosine/metabolism ; Adenosine/analogs & derivatives ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Amyotrophic Lateral Sclerosis/genetics
Chemical Substances	Methyltransferases (EC 2.1.1.-) ; Mettl3 protein, mouse (EC 2.1.1.-) ; DNA-Binding Proteins ; N-methyladenosine (CLE6G00625) ; Adenosine (K72T3FS567) ; METTL3 protein, human (EC 2.1.1.62)
Language	English
Publishing date	2024-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.113999
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Article ; Online: A hidden threshold in motor neuron gene networks revealed by modulation of miR-218 dose.

Amin, Neal D / Senturk, Gokhan / Costaguta, Giancarlo / Driscoll, Shawn / O'Leary, Brendan / Bonanomi, Dario / Pfaff, Samuel L

Neuron

2021 Volume 109, Issue 20, Page(s) 3252–3267.e6

Abstract: Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. ...

Abstract	Disruption of homeostatic microRNA (miRNA) expression levels is known to cause human neuropathology. However, the gene regulatory and phenotypic effects of altering a miRNA's in vivo abundance (rather than its binary gain or loss) are not well understood. By genetic combination, we generated an allelic series of mice expressing varying levels of miR-218, a motor neuron-selective gene regulator associated with motor neuron disease. Titration of miR-218 cellular dose unexpectedly revealed complex, non-ratiometric target mRNA dose responses and distinct gene network outputs. A non-linearly responsive regulon exhibited a steep miR-218 dose-dependent threshold in repression that, when crossed, resulted in severe motor neuron synaptic failure and death. This work demonstrates that a miRNA can govern distinct gene network outputs at different expression levels and that miRNA-dependent phenotypes emerge at particular dose ranges because of hidden regulatory inflection points of their underlying gene networks.
MeSH term(s)	Animals ; Gene Dosage ; Gene Regulatory Networks/genetics ; Mice ; Mice, Knockout ; MicroRNAs/genetics ; Motor Neuron Disease/genetics ; Motor Neurons/metabolism ; Sequence Analysis, RNA ; Single-Cell Analysis
Chemical Substances	MIRN218 microRNA, mouse ; MicroRNAs
Language	English
Publishing date	2021-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2021.07.028
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Structured wound angiogenesis instructs mesenchymal barrier compartments in the regenerating nerve.

Bhat, Ganesh Parameshwar / Maurizio, Aurora / Motta, Alessia / Podini, Paola / Diprima, Santo / Malpighi, Chiara / Brambilla, Ilaria / Martins, Luis / Badaloni, Aurora / Boselli, Daniela / Bianchi, Francesca / Pellegatta, Marta / Genua, Marco / Ostuni, Renato / Del Carro, Ubaldo / Taveggia, Carla / de Pretis, Stefano / Quattrini, Angelo / Bonanomi, Dario

Neuron

2023 Volume 112, Issue 2, Page(s) 209–229.e11

Abstract: Organ injury stimulates the formation of new capillaries to restore blood supply raising questions about the potential contribution of neoangiogenic vessel architecture to the healing process. Using single-cell mapping, we resolved the properties of ... ...

Abstract	Organ injury stimulates the formation of new capillaries to restore blood supply raising questions about the potential contribution of neoangiogenic vessel architecture to the healing process. Using single-cell mapping, we resolved the properties of endothelial cells that organize a polarized scaffold at the repair site of lesioned peripheral nerves. Transient reactivation of an embryonic guidance program is required to orient neovessels across the wound. Manipulation of this structured angiogenic response through genetic and pharmacological targeting of Plexin-D1/VEGF pathways within an early window of repair has long-term impact on configuration of the nerve stroma. Neovessels direct nerve-resident mesenchymal cells to mold a provisionary fibrotic scar by assembling an orderly system of stable barrier compartments that channel regenerating nerve fibers and shield them from the persistently leaky vasculature. Thus, guided and balanced repair angiogenesis enables the construction of a "bridge" microenvironment conducive for axon regrowth and homeostasis of the regenerated tissue.
MeSH term(s)	Endothelial Cells/metabolism ; Angiogenesis ; Peripheral Nerves/physiology ; Neovascularization, Physiologic ; Axons ; Nerve Regeneration/physiology
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.10.025
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: INTEGRATE: Model-based multi-omics data integration to characterize multi-level metabolic regulation.

Di Filippo, Marzia / Pescini, Dario / Galuzzi, Bruno Giovanni / Bonanomi, Marcella / Gaglio, Daniela / Mangano, Eleonora / Consolandi, Clarissa / Alberghina, Lilia / Vanoni, Marco / Damiani, Chiara

PLoS computational biology

2022 Volume 18, Issue 2, Page(s) e1009337

Abstract: Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net ...

Abstract	Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net rate of the reaction) for each enzyme-controlled reaction. On the other hand, metabolic regulation controls the metabolic flux through the interactions of metabolites (substrates, cofactors, allosteric modulators) with the responsible enzyme. High-throughput data, such as metabolomics and transcriptomics data, if analyzed separately, do not accurately characterize the hierarchical regulation of metabolism outlined above. They must be integrated to disassemble the interdependence between different regulatory layers controlling metabolism. To this aim, we propose INTEGRATE, a computational pipeline that integrates metabolomics and transcriptomics data, using constraint-based stoichiometric metabolic models as a scaffold. We compute differential reaction expression from transcriptomics data and use constraint-based modeling to predict if the differential expression of metabolic enzymes directly originates differences in metabolic fluxes. In parallel, we use metabolomics to predict how differences in substrate availability translate into differences in metabolic fluxes. We discriminate fluxes regulated at the metabolic and/or gene expression level by intersecting these two output datasets. We demonstrate the pipeline using a set of immortalized normal and cancer breast cell lines. In a clinical setting, knowing the regulatory level at which a given metabolic reaction is controlled will be valuable to inform targeted, truly personalized therapies in cancer patients.
MeSH term(s)	Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Computer Simulation ; Female ; Humans ; Metabolic Networks and Pathways ; Metabolomics ; Proof of Concept Study ; Proteomics ; Transcriptome
Language	English
Publishing date	2022-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1009337
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Article ; Online: Motor neurons use push-pull signals to direct vascular remodeling critical for their connectivity.

Martins, Luis F / Brambilla, Ilaria / Motta, Alessia / de Pretis, Stefano / Bhat, Ganesh Parameshwar / Badaloni, Aurora / Malpighi, Chiara / Amin, Neal D / Imai, Fumiyasu / Almeida, Ramiro D / Yoshida, Yutaka / Pfaff, Samuel L / Bonanomi, Dario

Neuron

2022 Volume 110, Issue 24, Page(s) 4090–4107.e11

Abstract: The nervous system requires metabolites and oxygen supplied by the neurovascular network, but this necessitates close apposition of neurons and endothelial cells. We find motor neurons attract vessels with long-range VEGF signaling, but endothelial cells ...

Abstract	The nervous system requires metabolites and oxygen supplied by the neurovascular network, but this necessitates close apposition of neurons and endothelial cells. We find motor neurons attract vessels with long-range VEGF signaling, but endothelial cells in the axonal pathway are an obstacle for establishing connections with muscles. It is unclear how this paradoxical interference from heterotypic neurovascular contacts is averted. Through a mouse mutagenesis screen, we show that Plexin-D1 receptor is required in endothelial cells for development of neuromuscular connectivity. Motor neurons release Sema3C to elicit short-range repulsion via Plexin-D1, thus displacing endothelial cells that obstruct axon growth. When this signaling pathway is disrupted, epaxial motor neurons are blocked from reaching their muscle targets and concomitantly vascular patterning in the spinal cord is altered. Thus, an integrative system of opposing push-pull cues ensures detrimental axon-endothelial encounters are avoided while enabling vascularization within the nervous system and along peripheral nerves.
MeSH term(s)	Animals ; Mice ; Vascular Remodeling ; Endothelial Cells/metabolism ; Motor Neurons/metabolism ; Axons/metabolism ; Spinal Cord/metabolism ; Semaphorins/metabolism
Chemical Substances	Semaphorins
Language	English
Publishing date	2022-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2022.09.021
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Ethnobotanical Documentation of the Uses of Wild and Cultivated Plants in the Ansanto Valley (Avellino Province, Southern Italy).

Motti, Riccardo / Marotta, Marco / Bonanomi, Giuliano / Cozzolino, Stefania / Di Palma, Anna

Plants (Basel, Switzerland)

2023 Volume 12, Issue 21

Abstract: With approximately 2800 species, the Campania region has the richest vascular flora in southern Italy and the highest number of medicinal species reported in the Italian folk traditions. The study area is inserted in a wide rural landscape, still ... ...

Abstract	With approximately 2800 species, the Campania region has the richest vascular flora in southern Italy and the highest number of medicinal species reported in the Italian folk traditions. The study area is inserted in a wide rural landscape, still retaining a high degree of naturalness and is studied for the first time from an ethnobotanical point of view. By analyzing local traditional uses of wild plants in the Ansanto Valley area, the present study aims to contribute to the implementation of ethnobotanical knowledge concerning southern Italy. To gather ethnobotanical knowledge related to the Ansanto Valley, 69 semi-structured interviews were carried out through a snowball sampling approach, starting from locals with experience in traditional plant uses (key informants). A number of 117 plant species (96 genera and 46 families) were documented for traditional use from a total of 928 reports, of which 544 were about medicinal plants. New use reports on the utilization of plants for medicinal (5) and veterinary applications (8) in the Campania region and the whole Italian territory were outlined from our investigations.
Language	English
Publishing date	2023-10-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704341-1
ISSN	2223-7747
ISSN	2223-7747
DOI	10.3390/plants12213690
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Article ; Online: INTEGRATE

Marzia Di Filippo / Dario Pescini / Bruno Giovanni Galuzzi / Marcella Bonanomi / Daniela Gaglio / Eleonora Mangano / Clarissa Consolandi / Lilia Alberghina / Marco Vanoni / Chiara Damiani

PLoS Computational Biology, Vol 18, Iss 2, p e

Model-based multi-omics data integration to characterize multi-level metabolic regulation.

2022 Volume 1009337

Abstract	Metabolism is directly and indirectly fine-tuned by a complex web of interacting regulatory mechanisms that fall into two major classes. On the one hand, the expression level of the catalyzing enzyme sets the maximal theoretical flux level (i.e., the net rate of the reaction) for each enzyme-controlled reaction. On the other hand, metabolic regulation controls the metabolic flux through the interactions of metabolites (substrates, cofactors, allosteric modulators) with the responsible enzyme. High-throughput data, such as metabolomics and transcriptomics data, if analyzed separately, do not accurately characterize the hierarchical regulation of metabolism outlined above. They must be integrated to disassemble the interdependence between different regulatory layers controlling metabolism. To this aim, we propose INTEGRATE, a computational pipeline that integrates metabolomics and transcriptomics data, using constraint-based stoichiometric metabolic models as a scaffold. We compute differential reaction expression from transcriptomics data and use constraint-based modeling to predict if the differential expression of metabolic enzymes directly originates differences in metabolic fluxes. In parallel, we use metabolomics to predict how differences in substrate availability translate into differences in metabolic fluxes. We discriminate fluxes regulated at the metabolic and/or gene expression level by intersecting these two output datasets. We demonstrate the pipeline using a set of immortalized normal and cancer breast cell lines. In a clinical setting, knowing the regulatory level at which a given metabolic reaction is controlled will be valuable to inform targeted, truly personalized therapies in cancer patients.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Italian pediatric intensive care units admitting critically ill cancer children: results from a national survey.

Minerva anestesiologica

2023 Volume 89, Issue 10, Page(s) 850–858

Abstract: Background: Pediatric patients affected by oncologic disease have a significant risk of clinical deterioration that requires admission to the intensive care unit. This study reported the results of a national survey describing the characteristics of ... ...

Abstract	Background: Pediatric patients affected by oncologic disease have a significant risk of clinical deterioration that requires admission to the intensive care unit. This study reported the results of a national survey describing the characteristics of Italian onco-hematological units (OHUs) and pediatric intensive care units (PICUs) that admit pediatric patients, focusing on the high-complexity treatments available before PICU admission, and evaluating the approach to the end-of-life (EOL) when cared in a PICU setting. Methods: A web-based electronic survey has been performed in April 2021, involving all Italian PICUs admitting pediatric patients with cancer participating in the study. Results: Eighteen PICUs participated, with a median number of admissions per year of 350 (IQR 248-495). Availability of Extracorporeal Membrane Oxygenation therapy and the presence of intermediate care unit are the only statistically different characteristics between large or small PICUs. Different high-level treatments and protocols are performed in OHUs, non depending on the volume of PICU. Palliative sedation is mainly performed in the OHUs (78%), however, in 72% it is also performed in the PICU. In most centers protocols that address EOL comfort care and treatment algorithms are missing, non depending on PICU or OHU volume. Conclusions: A non-homogeneous availability of high-level treatments and in OHUs is described. Moreover, protocols addressing EOL comfort care and treatment algorithms in palliative care are lacking in many centers.
MeSH term(s)	Child ; Humans ; Critical Illness/therapy ; Hospitalization ; Neoplasms/therapy ; Terminal Care ; Intensive Care Units, Pediatric
Language	English
Publishing date	2023-06-28
Publishing country	Italy
Document type	Journal Article
ZDB-ID	123584-9
ISSN	1827-1596 ; 0026-4717 ; 0375-9393
ISSN (online)	1827-1596
ISSN	0026-4717 ; 0375-9393
DOI	10.23736/S0375-9393.23.17329-9
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Zs.A 516: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Endothelial PlexinD1 signaling instructs spinal cord vascularization and motor neuron development.

Vieira, José Ricardo / Shah, Bhavin / Dupraz, Sebastian / Paredes, Isidora / Himmels, Patricia / Schermann, Géza / Adler, Heike / Motta, Alessia / Gärtner, Lea / Navarro-Aragall, Ariadna / Ioannou, Elena / Dyukova, Elena / Bonnavion, Remy / Fischer, Andreas / Bonanomi, Dario / Bradke, Frank / Ruhrberg, Christiana / Ruiz de Almodóvar, Carmen

Neuron

2022 Volume 110, Issue 24, Page(s) 4074–4089.e6

Abstract: How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we reveal a crosstalk between motor neurons (MNs) and endothelial cells (ECs), necessary ... ...

Abstract	How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we reveal a crosstalk between motor neurons (MNs) and endothelial cells (ECs), necessary for the coordinated development of MNs. By analyzing cell-to-cell interaction profiles of the mouse developing spinal cord, we uncovered semaphorin 3C (Sema3C) and PlexinD1 as a communication axis between MNs and ECs. Using cell-specific knockout mice and in vitro assays, we demonstrate that removal of Sema3C in MNs, or its receptor PlexinD1 in ECs, results in premature and aberrant vascularization of MN columns. Those vascular defects impair MN axon exit from the spinal cord. Impaired PlexinD1 signaling in ECs also causes MN maturation defects at later stages. This study highlights the importance of a timely and spatially controlled communication between MNs and ECs for proper spinal cord development.
MeSH term(s)	Animals ; Mice ; Endothelial Cells ; Motor Neurons/physiology ; Spinal Cord ; Signal Transduction ; Axons ; Mice, Knockout
Language	English
Publishing date	2022-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2022.12.005
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