Isabel Espinosa-Medina

Janelia Research Campus

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Tzumin Lee

Howard Hughes Medical Institute

Jorge García‐Marqués

Instituto Cajal

Minoru Koyama

Howard Hughes Medical Institute

Daniel Feliciano

Janelia Research Campus

Ching-Po Yang

Janelia Research Campus

Jean‐François Brunet

Bureau de Recherches Géologiques et Minières

Franck Boismoreau

Inserm

Zoubida Chettouh

Institut de Biologie de l'École Normale Supérieure

Rosa Linda Miyares

Janelia Research Campus

Ken Sugino

Helix (United States)

Cooperative Institutions

Howard Hughes Medical Institute

Janelia Research Campus

Helix (United States)

Inserm

Centre National de la Recherche Scientifique

George Washington University Virginia Campus

Institut de Biologie de l'École Normale Supérieure

Yale University

Harvard University

Université Paris Sciences et Lettres

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The “sacral parasympathetic”: ontogeny and anatomy of a myth

Clinical Autonomic Research (2017)

Isabel Espinosa-Medina Orthis Saha Franck Boismoreau Jean‐François Brunet

We recently defined genetic traits that distinguish sympathetic from parasympathetic neurons, both preganglionic and ganglionic (Espinosa-Medina et al., Science 354:893–897, 2016). By this set of criteria, we found that the sacral autonomic outflow is sympathetic, not parasympathetic as has been thought for more than a century. Proposing such a belated shift in perspective begs the question why the new criterion (cell types defined by their genetic make-up and dependencies) should be favored over the anatomical, physiological and pharmacological considerations of long ago that inspired the "parasympathetic" classification. After a brief reminder of the former, we expound the weaknesses of the latter and argue that the novel genetic definition helps integrating neglected anatomical and physiological observations and clearing the path for future research.

Parasympathetic nervous system

10.1007/s10286-017-0478-7

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Citations (31)

Deformable Registration of Whole Brain Zebrafish Microscopy Using an Implementation of the Flash Algorithm Within Ants

2022 IEEE 19th International Symposium on Biomedical Imaging (ISBI) (2019)

Greg Fleishman Miaomiao Zhang Nicholas J. Tustison Isabel Espinosa-Medina Yu Mu

Recent advancements in microscopy, protein engineering, and genetics have rendered the larval zerbrafish a powerful model system for which whole brain, real time, functional neuroimaging at cellular resolution is accessible. Supplementing functional data with additional modalities in the same fish such as structural connectivity and transcriptomics will enable interpretation of structure-function relationships across the entire brains of individual animals. However, proper identification of corresponding cells in the large image volumes produced depends on accurate and efficient deformable registration. To address this challenge, we implemented the Fourier-approximated Lie Algebras for Shooting (FLASH) algorithm within the well-known Advanced Normalization Tools (ANTs) package. This combines the speed of FLASH with the extensive set of image matching functionals and multi-staging multi-resolution capabilities of ANTs. We registered longitudinal data from nine fish, using a line that uniquely identifies subsets of neurons in an independent channel. We validate our approach by demonstrating accurate cell-to-cell correspondence while requiring significantly less time and memory than the Symmetric Normalization (SyN) implementation in ANTs, and without compromising the theoretical foundations of the Large Deformation Diffeomorphic Metric Mapping (LDDMM) model.

Neuroinformatics

Image registration

Normalization

Spatial normalization

10.1109/isbi.2019.8759549

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Citations (1)

Theoretical modeling on CRISPR-coded cell lineages: efficient encoding and optimal reconstruction

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Ken Sugino Jorge García‐Marqués Isabel Espinosa-Medina Tzumin Lee

Summary Delineating cell lineages is a prerequisite for understanding the genesis of cell types. Recent studies have demonstrated the feasibility of generating and reconstructing CRISPR/Cas9-coded cell lineages. However, these works have not investigated the limitations or optimality of the encoding or reconstruction processes. Here, we surveyed a multitude of reconstruction algorithms and found hierarchical clustering, with a metric based on the number of shared Cas9 edits, provides the best reconstruction. As to the efficiency, the simple encoding method, with constant Cas9/gRNA edit rate, produces exponential reduction in available coding units and severely limits the trackable depth of lineages. To overcome this, we propose alternative encoding methods, one based on parallel gRNA cascades enabled by CLADES, and another based on variable Cas9 editing rate. Both significantly increase the trackable depth. In summary, we provide a theoretical basis in understanding, designing and analyzing efficient and robust CRISPR-based cell lineage tracking system.

10.1101/538488

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Citations (9)

High-throughput dense reconstruction of cell lineages

Open Biology (2019)

Isabel Espinosa-Medina Jorge García‐Marqués Connie Cepko Tzumin Lee

The first meeting exclusively dedicated to the ‘High-throughput dense reconstruction of cell lineages' took place at Janelia Research Campus (Howard Hughes Medical Institute) from 14 to 18 April 2019. Organized by Tzumin Lee, Connie Cepko, Jorge Garcia-Marques and Isabel Espinosa-Medina, this meeting echoed the recent eruption of new tools that allow the reconstruction of lineages based on the phylogenetic analysis of DNA mutations induced during development. Combined with single-cell RNA sequencing, these tools promise to solve the lineage of complex model organisms at single-cell resolution. Here, we compile the conference consensus on the technological and computational challenges emerging from the use of the new strategies, as well as potential solutions.

Lineage (genetic)

Cell lineage

Garcia

10.1098/rsob.190229

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Citations (26)

The sacral autonomic outflow is sympathetic

Science (2016)

Isabel Espinosa-Medina Orthis Saha Franck Boismoreau Zoubida Chettouh Francesca Rossi

Sacral neurons reassigned The autonomic nervous system regulates the function of internal organs such as the gut. The parasympathetic and sympathetic arms of this system tend to operate antagonistically. Espinosa-Medina et al. used anatomical and molecular analyses to reevaluate the assignment of neurons in the sacral autonomic nervous system (see the Perspective by Adameyko). Previously categorized as parasympathetic, these neurons are now identified as sympathetic. The results resolve a persistent confusion about how the two systems developed and open the avenue to more predictable outcomes in developing treatments targeted to the pelvic autonomic nervous system. Science , this issue p. 893 ; see also p. 833

Sympathetic nervous system

Confusion

Parasympathetic nervous system

Autonomic function

10.1126/science.aah5454

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Citations (154)

TEMPO: A system to sequentially label and genetically manipulate vertebrate cell lineages

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Isabel Espinosa-Medina Daniel Feliciano Carla Belmonte‐Mateos Jorge García‐Marqués Benjamin R. Foster

Abstract During development, regulatory factors appear in a precise order to determine cell fates over time. To investigate complex tissue development, one should not just label cell lineages but further visualize and manipulate cells with temporal control. Current strategies for tracing vertebrate cell lineages lack genetic access to sequentially produced cells. Here we present TEMPO (Temporal Encoding and Manipulation in a Predefined Order), an imaging-readable genetic tool allowing differential labelling and manipulation of consecutive cell generations in vertebrates. TEMPO is based on CRISPR and powered by a cascade of gRNAs that drive orderly activation/inactivation of reporters/effectors. Using TEMPO to visualize zebrafish and mouse neurogenesis, we recapitulated birth-order-dependent neuronal fates. Temporally manipulating cell-cycle regulators in mouse cortex progenitors altered the proportion and distribution of neurons and glia, revealing the effects of temporal gene perturbation on serial cell fates. Thus, TEMPO enables sequential manipulation of molecular factors, crucial to study cell-type specification. One-Sentence Summary Gaining sequential genetic access to vertebrate cell lineages.

Cell type

Fate mapping

Cell fate determination

10.1101/2021.10.27.466134

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Citations (1)

Parasympathetic ganglia derive from Schwann cell precursors

Science (2014)

Isabel Espinosa-Medina E. Outin Christel Picard Zoubida Chettouh Susan M. Dymecki

Exploiting nervous paths already traveled The parasympathetic nervous system helps regulate the functions of many tissues and organs, including the salivary glands and the esophagus. To do so, it needs to reach throughout the body, connecting central systems to peripheral ones. Dyachuk et al. and Espinosa-Medina et al. explored how these connections are established in mice (see the Perspective by Kalcheim and Rohrer). Progenitor cells that travel along with the developing nerves can give rise to both myelinforming Schwann cells and to parasympathetic neurons. That means the interacting nerves do not have to find each other. Instead, the beginnings of the connections are laid down as the nervous system develops. Science , this issue p. 82 , p. 87 ; see also p. 32

Schwann cell

Dorsal root ganglion

Autonomic ganglion

Peripheral Nervous System

Parasympathetic nervous system

Cell bodies

Crest

10.1126/science.1253286

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Citations (191)

Dense reconstruction of elongated cell lineages: overcoming suboptimum lineage encoding and sparse cell sampling

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Ken Sugino Rosa Linda Miyares Isabel Espinosa-Medina Huimin Chen Christopher J. Potter

Abstract Acquiring both lineage and cell-type information during brain development could elucidate transcriptional programs underling neuronal diversification. This is now feasible with single-cell RNA-seq combined with CRISPR-based lineage tracing, which generates genetic barcodes with cumulative CRISPR edits. This technique has not yet been optimized to deliver high-resolution lineage reconstruction of protracted lineages. Drosophila neuronal lineages are an ideal model to consider, as multiple lineages have been morphologically mapped at single-cell resolution. Here we find the parameter ranges required to encode a representative neuronal lineage emanating from 100 stem cell divisions. We derive the optimum editing rate to be inversely proportional to lineage depth, enabling encoding to persist across lineage progression. Further, we experimentally determine the editing rates of a Cas9-deaminase in cycling neural stem cells, finding near ideal rates to map elongated Drosophila neuronal lineages. Moreover, we propose and evaluate strategies to separate recurring cell-types for lineage reconstruction. Finally, we present a simple method to combine multiple experiments, which permits dense reconstruction of protracted cell lineages despite suboptimum lineage encoding and sparse cell sampling.

Lineage (genetic)

Cell lineage

Cell type

10.1101/2020.07.27.223321

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Citations (2)

TEMPO enables sequential genetic labeling and manipulation of vertebrate cell lineages

Neuron (2022)

Isabel Espinosa-Medina Daniel Feliciano Carla Belmonte‐Mateos Rosa Linda Miyares Jorge García‐Marqués

During development, regulatory factors appear in a precise order to determine cell fates over time. Consequently, to investigate complex tissue development, it is necessary to visualize and manipulate cell lineages with temporal control. Current strategies for tracing vertebrate cell lineages lack genetic access to sequentially produced cells. Here, we present TEMPO (Temporal Encoding and Manipulation in a Predefined Order), an imaging-readable genetic tool allowing differential labeling and manipulation of consecutive cell generations in vertebrates. TEMPO is based on CRISPR and powered by a cascade of gRNAs that drive orderly activation and inactivation of reporters and/or effectors. Using TEMPO to visualize zebrafish and mouse neurogenesis, we recapitulated birth-order-dependent neuronal fates. Temporally manipulating cell-cycle regulators in mouse cortex progenitors altered the proportion and distribution of neurons and glia, revealing the effects of temporal gene perturbation on serial cell fates. Thus, TEMPO enables sequential manipulation of molecular factors, crucial to study cell-type specification.

10.1016/j.neuron.2022.10.035

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Citations (5)

Design and Generation of TEMPO Reagents for Sequential Labeling and Manipulation of Vertebrate Cell Lineages

Methods in molecular biology (2025)

Isabel Espinosa-Medina

10.1007/978-1-0716-4310-5_17

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Citations (0)