Biology subjects

Maduro, M. F.

Publications and source records attributed to Maduro, M. F..

3 recordsLinked to original sources

bioRxiv2022

The ELT-3 GATA Factor Specifies Endoderm in Caenorhabditis angaria in an ancestral gene network

Endoderm specification in the nematode, C. elegans, occurs through a well-characterized pathway that is initiated by maternally provided SKN-1/Nrf, and with additional input from POP-1/TCF, which activates the GATA factor cascade MED-1,2 [->] END-1,3 [->] ELT-2,7. Orthologues of the MED and END factors, and ELT-7, are found only among nematodes of the Elegans Supergroup consisting of species closely related to C. elegans, which raises the question of how gut is specified in their absence. In this work, we investigate gut specification outside the Elegans Supergroup. We find that the C. angaria and C. portoensis orthologues of the elt-3 GATA factor gene are expressed in the early E lineage, just before their elt-2 orthologues. In C. angaria, both Can-pop-1(RNAi) and Can-elt-3(RNAi) result in a penetrant gutless phenotype. Can-pop-1 is necessary for Can-elt-3 activation, showing that it acts upstream. When introduced into C. elegans as transgenes, overexpressed Can-elt-3 is sufficient to specify gut, while Can-elt-2 can rescue gut differentiation under the control of its own promoter. Our results demonstrate an ancestral mechanism for gut specification and differentiation in Caenorhabditis involving a simplified gene network consisting of POP-1 [->] ELT-3 [->] ELT-2. Summary statementSpecification of the gut progenitor E in a distant relative of C. elegans uses a different GATA factor, ELT-3, suggesting that the ancestral network was simpler.

developmental biology↗

bioRxiv2021

Recursive feedforward regulatory logic underlies robustness of the specification-to-differentiation transition and fidelity of terminal cell fate during C. elegans endoderm development

Development is driven by gene regulatory networks (GRNs) that progressively dictate specification and differentiation of cell fates. The architecture of GRNs directly determines the specificity and accuracy of developmental outcomes. We report here that the core regulatory circuitry for endoderm development in C. elegans is comprised of a recursive series of interlocked feedforward modules linking a cascade of six sequentially expressed GATA-type transcription factors. This structure results in a reiterated sequential redundancy, in which removal of a single factor or alternate factors in the cascade results in no, or a mild, effect on endoderm development and gut differentiation, while elimination of any two factors that are sequentially deployed in the cascade invariably results in a strong phenotype. The strength of the observed phenotypes is successfully predicted by a computational model based on the timing and levels of transcriptional states. The feedforward regulatory logic in the GRN appears to ensure timely onset of terminal differentiation genes and allows rapid and robust lockdown of cell fate during early embryogenesis. We further found that specification-to-differentiation transition is linked through a common regulator, the END-1 GATA factor that straddles the two processes. Finally, we revealed roles for key GATA factors in establishing spatial regulatory state domains by acting as transcriptional repressors that appear to define the boundaries of the digestive tract. Our findings support a comprehensive model of the core gene network that describes how robust endoderm development is achieved during C. elegans embryogenesis. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/457588v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@8515d6org.highwire.dtl.DTLVardef@15ca234org.highwire.dtl.DTLVardef@9d0fe7org.highwire.dtl.DTLVardef@17f28db_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2019

Evolutionary dynamics of the SKN-1 -> MED -> END-1,3 regulatory gene cascade in Caenorhabditis endoderm specification

Gene regulatory networks (GRNs) with GATA factors are important in animal development, and evolution of such networks is an important problem in the field. In the nematode, Caenorhabditis elegans, the endoderm (gut) is generated from a single embryonic precursor, E. The gut is specified by an essential cascade of transcription factors in a GRN, with the maternal factor SKN-1 at the top, activating expression of the redundant med-1,2 divergent GATA factor genes, with the combination of all three contributing to activation of the paralogous end-3 and end-1 canonical GATA factor genes. In turn, these factors activate the GATA factors genes elt-2 and elt-7 to regulate intestinal fate. In this work, genome sequences from over two dozen species within the Caenorhabditis genus are used to identify putative orthologous genes encoding the MED and END-1,3 factors. The predictions are validated by comparison of gene structure, protein conservation, and putative cis-regulatory sites. The results show that all three factors occur together, but only within the Elegans supergroup of related species. While all three factors share similar DNA-binding domains, the MED factors are the most diverse as a group and exhibit unexpectedly high gene amplifications, while the END-1 orthologs are highly conserved and share additional extended regions of conservation not found in the other GATA factors. The MEME algorithm identified both known and previously unrecognized cis-regulatory motifs. The results suggest that all three genes originated at the base of the Elegans supergroup and became fixed as an essential embryonic gene regulatory network with several conserved features, although each of the three factors is under different evolutionary constraints. Based on the results, a model for the origin and evolution of the network is proposed. The set of identified MED, END-3 and END-1 factors form a robust set of factors defining an essential embryonic gene network that has been conserved for tens of millions of years, that will serve as a basis for future studies of GRN evolution.

genetics↗