The fetal-maternal interface across species: from comparative embryology to multicellular systems

The tissue microenvironment cooperates with intrinsic molecular regulators to model cell identity and plasticity. In the Gerri lab, we are interested in studying how cell lineages are established, and how they communicate with each other and the surrounding microenvironment to build an organ. Our goal is to understand how the environmental cues and the neighbouring tissues influence early cell fate decisions, and how progenitor cells interpret these signals and react, thereby affecting their surroundings. We aim to study a very enigmatic process of mammalian reproduction: the development of the placenta. By investigating the formation of the fetal placental progenitors and their interactions with the maternal tissues, we hope to understand the principles orchestrating this unique biunivocal crosstalk regulating cell specification and differentiation in two distinct organisms. 

To achieve these fundamental questions, we leverage mammalian preimplantation embryos, genetics and quantitative confocal imaging. In addition, we are also using 3D organoid culture systems, live imaging and microfluidics to model placenta development in vitro.

To gain further mechanistic insights, we would also like to collaborate closely with biophysicists as well as computer scientists at the MPI-CBG and the Dresden Campus.

We believe that understanding the interplay between cell fate specification, external microenvironmental cues and tissue scale forces is essential to uncover the principles underlying robust organ morphogenesis during development.

Selected publications

* joined first author # joined corresponding author

Claudia Gerri, Afshan McCarthy, Gregorio Alanis-Lobato, Andrej Demtschenko, Alexandre Bruneau, Sophie Loubersac, Norah M E Fogarty, Daniel Hampshire, Kay Elder, Phil Snell, Leila Christie, Laurent David, Hilde Van de Velde, Ali A Fouladi-Nashta, Kathy K Niakan
Initiation of a conserved trophectoderm program in human, cow and mouse embryos.
Nature, 587(7834) 443-447 (2020)
Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event occurs at the morula stage, with outer cells initiating a trophectoderm (TE) placental progenitor program. The inner cell mass arises from inner cells during subsequent developmental stages and comprises precursor cells of the embryo proper and yolk sac1. Recent gene-expression analyses suggest that the mechanisms that regulate early lineage specification in the mouse may differ in other mammals, including human2-5 and cow6. Here we show the evolutionary conservation of a molecular cascade that initiates TE segregation in human, cow and mouse embryos. At the morula stage, outer cells acquire an apical-basal cell polarity, with expression of atypical protein kinase C (aPKC) at the contact-free domain, nuclear expression of Hippo signalling pathway effectors and restricted expression of TE-associated factors such as GATA3, which suggests initiation of a TE program. Furthermore, we demonstrate that inhibition of aPKC by small-molecule pharmacological modulation or Trim-Away protein depletion impairs TE initiation at the morula stage. Our comparative embryology analysis provides insights into early lineage specification and suggests that a similar mechanism initiates a TE program in human, cow and mouse embryos.

Claudia Gerri✳︎, Sergio Menchero✳︎, Shantha K Mahadevaiah, James M A Turner#, Kathy K Niakan#
Human Embryogenesis: A Comparative Perspective.
Annu Rev Cell Dev Biol, 36 411-440 (2020)
Understanding human embryology has historically relied on comparative approaches using mammalian model organisms. With the advent of low-input methods to investigate genetic and epigenetic mechanisms and efficient techniques to assess gene function, we can now study the human embryo directly. These advances have transformed the investigation of early embryogenesis in nonrodent species, thereby providing a broader understanding of conserved and divergent mechanisms. Here, we present an overview of the major events in human preimplantation development and place them in the context of mammalian evolution by comparing these events in other eutherian and metatherian species. We describe the advances of studies on postimplantation development and discuss stem cell models that mimic postimplantation embryos. A comparative perspective highlights the importance of analyzing different organisms with molecular characterization and functional studies to reveal the principles of early development. This growing field has a fundamental impact in regenerative medicine and raises important ethical considerations.

Claudia Gerri✳︎, Michele Marass✳︎, Andrea Rossi, Didier Y.R. Stainier
Hif-1α and Hif-2α regulate hemogenic endothelium and hematopoietic stem cell formation in zebrafish.
Blood, 131(9) 963-973 (2018)
During development, hematopoietic stem cells (HSCs) derive from specialized endothelial cells (ECs) called hemogenic endothelium (HE) via a process called endothelial-to-hematopoietic transition (EHT). Hypoxia-inducible factor-1α (HIF-1α) has been reported to positively modulate EHT in vivo, but current data indicate the existence of other regulators of this process. Here we show that in zebrafish, Hif-2α also positively modulates HSC formation. Specifically, HSC marker gene expression is strongly decreased in hif-1aa;hif-1ab (hif-1α) and in hif-2aa;hif-2ab (hif-2α) zebrafish mutants and morphants. Moreover, live imaging studies reveal a positive role for hif-1α and hif-2α in regulating HE specification. Knockdown of hif-2α in hif-1α mutants leads to a greater decrease in HSC formation, indicating that hif-1α and hif-2α have partially overlapping roles in EHT. Furthermore, hypoxic conditions, which strongly stimulate HSC formation in wild-type animals, have little effect in the combined absence of Hif-1α and Hif-2α function. In addition, we present evidence for Hif and Notch working in the same pathway upstream of EHT. Both notch1a and notch1b mutants display impaired EHT, which cannot be rescued by hypoxia. However, overexpression of the Notch intracellular domain in ECs is sufficient to rescue the hif-1α and hif-2α morphant EHT phenotype, suggesting that Notch signaling functions downstream of the Hif pathway during HSC formation. Altogether, our data provide genetic evidence that both Hif-1α and Hif-2α regulate EHT upstream of Notch signaling.

Claudia Gerri, Rubén Marín-Juez, Michele Marass, Alora Marks, Hans-Martin Maischein, Didier Y.R. Stainier
Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish.
Nat Commun, 8 Art. No. 15492 (2017)
Open Access DOI
Macrophages are known to interact with endothelial cells during developmental and pathological angiogenesis but the molecular mechanisms modulating these interactions remain unclear. Here, we show a role for the Hif-1α transcription factor in this cellular communication. We generated hif-1aa;hif-1ab double mutants in zebrafish, hereafter referred to as hif-1α mutants, and find that they exhibit impaired macrophage mobilization from the aorta-gonad-mesonephros (AGM) region as well as angiogenic defects and defective vascular repair. Importantly, macrophage ablation is sufficient to recapitulate the vascular phenotypes observed in hif-1α mutants, revealing for the first time a macrophage-dependent angiogenic process during development. Further substantiating our observations of vascular repair, we find that most macrophages closely associated with ruptured blood vessels are Tnfα-positive, a key feature of classically activated macrophages. Altogether, our data provide genetic evidence that Hif-1α regulates interactions between macrophages and endothelial cells starting with the mobilization of macrophages from the AGM.

Andrea Rossi✳︎, Zacharias Kontarakis✳︎, Claudia Gerri, Hendrik Nolte, Soraya Hölper, Marcus Krüger, Didier Y.R. Stainier
Genetic compensation induced by deleterious mutations but not gene knockdowns.
Nature, 524(7564) 230-233 (2015)
Cells sense their environment and adapt to it by fine-tuning their transcriptome. Wired into this network of gene expression control are mechanisms to compensate for gene dosage. The increasing use of reverse genetics in zebrafish, and other model systems, has revealed profound differences between the phenotypes caused by genetic mutations and those caused by gene knockdowns at many loci, an observation previously reported in mouse and Arabidopsis. To identify the reasons underlying the phenotypic differences between mutants and knockdowns, we generated mutations in zebrafish egfl7, an endothelial extracellular matrix gene of therapeutic interest, as well as in vegfaa. Here we show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl7 morpholino (morphants) exhibit severe vascular defects. We further observe that egfl7 mutants are less sensitive than their wild-type siblings to Egfl7 knockdown, arguing against residual protein function in the mutants or significant off-target effects of the morpholinos when used at a moderate dose. Comparing egfl7 mutant and morphant proteomes and transcriptomes, we identify a set of proteins and genes that are upregulated in mutants but not in morphants. Among them are extracellular matrix genes that can rescue egfl7 morphants, indicating that they could be compensating for the loss of Egfl7 function in the phenotypically wild-type egfl7 mutants. Moreover, egfl7 CRISPR interference, which obstructs transcript elongation and causes severe vascular defects, does not cause the upregulation of these genes. Similarly, vegfaa mutants but not morphants show an upregulation of vegfab. Taken together, these data reveal the activation of a compensatory network to buffer against deleterious mutations, which was not observed after translational or transcriptional knockdown.