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Xbp1 and Brachyury establish an evolutionarily conserved subcircuit of the notochord gene regulatory network

Wu, Yushi; Devotta, Arun; José-Edwards, Diana S; Kugler, Jamie E; Negrón-Piñeiro, Lenny J; Braslavskaya, Karina; Addy, Jermyn; Saint-Jeannet, Jean-Pierre; Di Gregorio, Anna
Gene regulatory networks coordinate the formation of organs and structures that compose the evolving body plans of different organisms. We are using a simple chordate model, the Ciona embryo, to investigate the essential gene regulatory network that orchestrates morphogenesis of the notochord, a structure necessary for the proper development of all chordate embryos. Although numerous transcription factors expressed in the notochord have been identified in different chordates, several of them remain to be positioned within a regulatory framework. Here, we focus on Xbp1, a transcription factor expressed during notochord formation in Ciona and other chordates. Through the identification of Xbp1-downstream notochord genes in Ciona, we found evidence of the early co-option of genes involved in the unfolded protein response to the notochord developmental program. We report the regulatory interplay between Xbp1 and Brachyury, and by extending these results to Xenopus, we show that Brachyury and Xbp1 form a cross-regulatory subcircuit of the notochord gene regulatory network that has been consolidated during chordate evolution.
PMID: 35049502
ISSN: 2050-084x
CID: 5157112

The Degenerate Tale of Ascidian Tails

Fodor, Alexander C A; Powers, Megan M; Andrykovich, Kristin; Liu, Jiatai; Lowe, Elijah K; Brown, C Titus; Di Gregorio, Anna; Stolfi, Alberto; Swalla, Billie J
Ascidians are invertebrate chordates, with swimming chordate tadpole larvae that have distinct heads and tails. The head contains the small brain, sensory organs, including the ocellus (light) and otolith (gravity) and the presumptive endoderm, while the tail has a notochord surrounded by muscle cells and a dorsal nerve cord. One of the chordate features is a post-anal tail. Ascidian tadpoles are nonfeeding, but their tail is critical for larval locomotion. After hatching the larvae swim up towards light and are carried by the tide and ocean currents. When competent to settle, ascidian tadpole larvae swim down, away from light, to settle and metamorphose into a sessile adult. Tunicates are classified as chordates because of their chordate tadpole larvae; in contrast, the sessile adult has a U-shaped gut and very derived body plan, looking nothing like a chordate. There is one group of ascidians, the Molgulidae, where many species are known to have tailless larvae. The Swalla Lab has been studying the evolution of tailless ascidian larvae in this clade for over thirty years and has shown that tailless larvae have evolved independently several times in this clade. Comparison of the genomes of two closely related species, the tailed Molgula oculata and tailless Molgula occulta reveals much synteny, but there have been multiple insertions and deletions that have disrupted larval genes in the tailless species. Genomics and transcriptomics have previously shown that there are expressed pseudogenes in the tailless embryos, suggesting that the partial rescue of tailed features in their hybrid larvae is due to the expression of intact genes from the tailed parent. Yet surprisingly, we find that the notochord gene regulatory network is mostly intact in the tailless M. occulta, although the notochord does not converge and extend and remains as an aggregate of cells we call the "notoball". We expect that eventually many of the larval gene networks will be become evolutionarily lost in tailless ascidians and the larval body plan abandoned, with eggs developing directly into an adult. Here we review the current evolutionary and developmental evidence on how the molgulids lost their tails.
PMID: 33881514
ISSN: 1557-7023
CID: 4847162

Cis-regulatory control of stage-specific notochord gene expression by Brachyury [Meeting Abstract]

Negron-Pineiro, L. J.; Di Gregorio, A.
ISSN: 1540-7063
CID: 4892382

Transcription Factors of the bHLH Family Delineate Vertebrate Landmarks in the Nervous System of a Simple Chordate

Negron-Pineiro, Lenny J; Wu, Yushi; Di Gregorio, Anna
Tunicates are marine invertebrates whose tadpole-like larvae feature a highly simplified version of the chordate body plan. Similar to their distant vertebrate relatives, tunicate larvae develop a regionalized central nervous system and form distinct neural structures, which include a rostral sensory vesicle, a motor ganglion, and a caudal nerve cord. The sensory vesicle contains a photoreceptive complex and a statocyst, and based on the comparable expression patterns of evolutionarily conserved marker genes, it is believed to include proto-hypothalamic and proto-retinal territories. The evolutionarily conserved molecular fingerprints of these landmarks of the vertebrate brain consist of genes encoding for different transcription factors, and of the gene batteries that they control, and include several members of the bHLH family. Here we review the complement of bHLH genes present in the streamlined genome of the tunicate Ciona robusta and their current classification, and summarize recent studies on proneural bHLH transcription factors and their expression territories. We discuss the possible roles of bHLH genes in establishing the molecular compartmentalization of the enticing nervous system of this unassuming chordate.
PMID: 33114624
ISSN: 2073-4425
CID: 4652512

The notochord gene regulatory network in chordate evolution: Conservation and divergence from Ciona to vertebrates

Di Gregorio, Anna
The notochord is a structure required for support and patterning of all chordate embryos, from sea squirts to humans. An increasing amount of information on notochord development and on the molecular strategies that ensure its proper morphogenesis has been gleaned through studies in the sea squirt Ciona. This invertebrate chordate offers a fortunate combination of experimental advantages, ranging from translucent, fast-developing embryos to a compact genome and impressive biomolecular resources. These assets have enabled the rapid identification of numerous notochord genes and cis-regulatory regions, and provide a rather unique opportunity to reconstruct the gene regulatory network that controls the formation of this developmental and evolutionary chordate landmark. This chapter summarizes the morphogenetic milestones that punctuate notochord formation in Ciona, their molecular effectors, and the current knowledge of the gene regulatory network that ensures the accurate spatial and temporal orchestration of these processes.
PMID: 32450965
ISSN: 1557-8933
CID: 4451572

Positioning a multifunctional basic helix-loop-helix transcription factor within the Ciona notochord gene regulatory network

Kugler, Jamie E; Wu, Yushi; Katikala, Lavanya; Passamaneck, Yale J; Addy, Jermyn; Caballero, Natalia; Oda-Ishii, Izumi; Maguire, Julie E; Li, Raymond; Di Gregorio, Anna
In a multitude of organisms, transcription factors of the basic helix-loop-helix (bHLH) family control the expression of genes required for organ development and tissue differentiation. The functions of different bHLH transcription factors in the specification of nervous system and paraxial mesoderm have been widely investigated in various model systems. Conversely, the knowledge of the role of these regulators in the development of the axial mesoderm, the embryonic territory that gives rise to the notochord, and the identities of their target genes, remain still fragmentary. Here we investigated the transcriptional regulation and target genes of Bhlh-tun1, a bHLH transcription factor expressed in the developing Ciona notochord as well as in additional embryonic territories that contribute to the formation of both larval and adult structures. We describe its possible role in notochord formation, its relationship with the key notochord transcription factor Brachyury, and suggest molecular mechanisms through which Bhlh-tun1 controls the spatial and temporal expression of its effectors.
PMID: 30661645
ISSN: 1095-564x
CID: 3610202

Tunicates: From humble sea squirt to proud model organism [Editorial]

Irvine, Steven Q; Ristoratore, Filomena; Di Gregorio, Anna
PMID: 30803728
ISSN: 1095-564x
CID: 3698962

Investigating Evolutionarily Conserved Molecular Mechanisms Controlling Gene Expression in the Notochord

Maguire, Julie E; Pandey, Aakarsha; Wu, Yushi; Di Gregorio, Anna
Ascidian embryos have been employed as model systems for studies of developmental biology for well over a century, owing to their desirable blend of experimental advantages, which include their rapid development, traceable cell lineage, and evolutionarily conserved morphogenetic movements. Two decades ago, the development of a streamlined electroporation method drastically reduced the time and cost of transgenic experiments, and, along with the elucidation of the complete genomic sequences of several ascidian species, propelled these simple chordates to the forefront of the model organisms available for studies of regulation of gene expression. Numerous ascidian sequences with tissue-specific enhancer activity were isolated and rapidly characterized through systematic in vivo experiments that would require several weeks in most other model systems. These cis-regulatory sequences include a large collection of notochord enhancers, which have been used to visualize notochord development in vivo, to generate mutant phenotypes, and to knock down genes of interest. Moreover, their detailed characterization has allowed the reconstruction of different branches of the notochord gene regulatory network. This chapter describes how the use of transgenic techniques has rendered the ascidian Ciona a competitive model organism for studies of notochord development, evolution, and gene regulation.
PMID: 29542082
ISSN: 0065-2598
CID: 2992962

T-Box Genes and Developmental Gene Regulatory Networks in Ascidians

Di Gregorio, A
Ascidians are invertebrate chordates with a biphasic life cycle characterized by a dual body plan that displays simplified versions of chordate structures, such as a premetamorphic 40-cell notochord topped by a dorsal nerve cord and postmetamorphic pharyngeal slits. These relatively simple chordates are characterized by rapid development, compact genomes and ease of transgenesis, and thus provide the opportunity to rapidly characterize the genomic organization, developmental function, and transcriptional regulation of evolutionarily conserved gene families. This review summarizes the current knowledge on members of the T-box family of transcription factors in Ciona and other ascidians. In both chordate and nonchordate animals, these genes control a variety of morphogenetic processes, and their mutations are responsible for malformations and developmental defects in organisms ranging from flies to humans. In ascidians, T-box transcription factors are required for the formation and specialization of essential structures, including notochord, muscle, heart, and differentiated neurons. In recent years, the experimental advantages offered by ascidian embryos have allowed the rapid accumulation of a wealth of information on the molecular mechanisms that regulate the expression of T-box genes. These studies have also elucidated the strategies employed by these transcription factors to orchestrate the appropriate spatial and temporal deployment of the numerous target genes that they control.
PMID: 28057272
ISSN: 1557-8933
CID: 2387012

ANISEED 2015: a digital framework for the comparative developmental biology of ascidians

Brozovic, Matija; Martin, Cyril; Dantec, Christelle; Dauga, Delphine; Mendez, Mickael; Simion, Paul; Percher, Madeline; Laporte, Baptiste; Scornavacca, Celine; Di Gregorio, Anna; Fujiwara, Shigeki; Gineste, Mathieu; Lowe, Elijah K; Piette, Jacques; Racioppi, Claudia; Ristoratore, Filomena; Sasakura, Yasunori; Takatori, Naohito; Brown, Titus C; Delsuc, Frederic; Douzery, Emmanuel; Gissi, Carmela; McDougall, Alex; Nishida, Hiroki; Sawada, Hitoshi; Swalla, Billie J; Yasuo, Hitoyoshi; Lemaire, Patrick
Ascidians belong to the tunicates, the sister group of vertebrates and are recognized model organisms in the field of embryonic development, regeneration and stem cells. ANISEED is the main information system in the field of ascidian developmental biology. This article reports the development of the system since its initial publication in 2010. Over the past five years, we refactored the system from an initial custom schema to an extended version of the Chado schema and redesigned all user and back end interfaces. This new architecture was used to improve and enrich the description of Ciona intestinalis embryonic development, based on an improved genome assembly and gene model set, refined functional gene annotation, and anatomical ontologies, and a new collection of full ORF cDNAs. The genomes of nine ascidian species have been sequenced since the release of the C. intestinalis genome. In ANISEED 2015, all nine new ascidian species can be explored via dedicated genome browsers, and searched by Blast. In addition, ANISEED provides full functional gene annotation, anatomical ontologies and some gene expression data for the six species with highest quality genomes. ANISEED is publicly available at:
PMID: 26420834
ISSN: 1362-4962
CID: 1899892