Biology subjects

Wehmeyer, A. E.

Publications and source records attributed to Wehmeyer, A. E..

4 recordsLinked to original sources

bioRxiv2025

Competing regulatory modules control the transition between mammalian gastrulation modes

During mammalian gastrulation cells of the primary germ layers are generated in anterior-to-posterior sequence employing different morphogenetic modes. Initial gastrulation is characterized by cell ingression through the early primitive streak, followed by posterior embryonic axis elongation via cell recruitment from progenitor pools. Molecular details of different genetic programs controlling early and late gastrulation remain ill described. Here, we employed stem cell-based mouse gastruloids to reveal two consecutively acting regulatory modules that orchestrate spatiotemporal progression of gastrulation. The early anterior module consists of the Tbx transcription factor Eomes, and signalling molecules Nodal and Wnt3 that initiate gastrulation and generate anterior mesoderm and definitive endoderm from the early streak. The anterior module represses the second, Tbxt/Wnt3a posterior regulatory module controlling axial extension at trunk levels. Both circuitries are self-reinforcing while mutually repressing the counteracting module at multiple levels as the molecular basis for the spatiotemporal progression of gastrulation along the AP axis.

developmental biology↗

bioRxiv2025

A temporal coordination between Nodal and Wnt signalling governs the emergence of the mammalian body plan

Nodal and Wnt signalling play an important role in the emergence of the mammalian body plan, primarily by orchestrating gastrulation. While the literature suggests they cooperate to build the primitive streak, their individual contributions remain poorly understood. Using gastruloids, we found that Wnt/{beta}-catenin drives a genetic program characteristic of the late primitive streak, promoting the development of posterior body structures in a time and dose-dependent manner. Conversely, Nodal activates a distinct transcriptional module resembling the early streak. By engineering gastruloids with varying levels of Nodal signalling, we demonstrate that a decreasing temporal gradient of Nodal activity is critical for establishing the anterior body, with higher Nodal levels producing more anterior structures in a concentration-dependent manner. Our findings suggest that Nodal and Wnt act antagonistically, initiating distinct developmental modules within the primitive streak. This antagonism is likely the core mechanism driving the early body plan in mammals.

developmental biology↗

bioRxiv2023

Eomes restricts Brachyury functions at the onset of mammalian gastrulation

Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin (Eomes) and Brachyury sharing partially redundant functions. Gross differences of mutant embryonic phenotypes suggest specific functions of each TF. To date, the molecular details of separated lineage-specific gene-regulation by Eomes and Brachyury remain poorly understood. Here, we combine embryonic and stem cell-based analyses to delineate the non-overlapping, lineage-specific transcriptional activities. On a genome-wide scale binding of both TFs overlaps at promoters of target genes, but shows specificity for distal enhancer regions, that is conferred by differences in Tbx DNA-binding motifs. The unique binding to enhancer sites instructs the specification of anterior mesoderm (AM) and DE by Eomes and caudal mesoderm by Brachyury. Remarkably, EOMES antagonizes BRACHYURY gene-regulatory functions in co-expressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives. HighlightsO_LIDetailed comparative analysis of the two critical developmental regulators Eomes and Brachyury in mouse embryos and differentiating embryonic stem cells C_LIO_LITbx factors EOMES and BRACHYURY control distinct gene programs to specify different mesoderm and endoderm subsets C_LIO_LIProgram specificity is conferred by binding to non-overlapping enhancers with distinct binding motifs C_LIO_LIEOMES restricts the activities of BRACHYURY thus ensuring the proper sequence of mesoderm and endoderm lineage specification C_LI

developmental biology↗

bioRxiv2022

Chimeric 3D-gastruloids - a versatile tool for studies of mammalian peri-gastrulation development

Stem cell-derived 3D-gastruloids show a remarkable capacity of self-organisation and recapitulate many aspects of gastrulation stage mammalian development. Gastruloids can be rapidly generated and offer several experimental advantages, such as scalability, observability, and accessibility for manipulation. Here, we present approaches to further expand the experimental potency of murine 3D-gastruloids by utilizing functional genetics in mouse embryonic stem cells (mESCs) to generate chimeric gastruloids. In chimeric gastruloids fluorescently labelled cells of different genotypes harbouring inducible gene-expression, or loss-of-function alleles, are combined with wildtype cells. We showcase this experimental approach in chimeric gastruloids of mESCs carrying homozygous deletions of the Tbx transcription factors Brachyury, or inducible expression of Eomes. Resulting chimeric gastruloids recapitulate reported Eomes and Brachyury functions, such as instructing cardiac fate and promoting posterior axial extension, respectively. Additionally, chimeric gastruloids revealed previously unrecognized phenotypes such as tissue sorting preference of Brachyury-deficient cells to endoderm, and cell non-autonomous effects of Brachyury-deficiency on Wnt3a-patterning along the embryonic axis, demonstrating some of the advantages of chimeric gastruloids as efficient tool for studies of mammalian gastrulation.

developmental biology↗