In memoriam: Bernard Thisse (August 26, 1959 - December 16, 2021)

Dr Bernard THISSE,

Directeur de Recherche au CNRS, France

Professor of Cell Biology and Biology, Cell Biology Department, UVA, Charlottesville,

USA

 

In memory of Bernard

December 30th, 2021

 

Dear All,

This is the saddest letter I ever wrote in my life. Bernard passed away recently. He was

diagnosed the last day of 2020 with a very aggressive lymphoma. He fought during 16 months,

trying every treatment that was available. He took this journey, fighting without complaining.

But he did not win the battle. I miss him terribly. All of us (friends, family, trainees, colleagues)

miss him. He was passionate by about many topics in Science, but also has strong interests in

Philosophy, Astronomy, Physics, History, Art, Operas and … Politics. Where he felt the best

was outdoor. He was a serious biker and hiker, in love with mountains and forests.

 

Bernard always challenged himself and us all around him. He had to answer his

questions, he never gave up, worked like crazy and wanted perfection in all he was doing. No

way he would accept a poor image or a crapy gel. He had a bright mind and was able to get

out his field (e.g.: circadian rhythm, morphogenesis in vitro using a mouse embryonic stem

cell model) with the same success that the ‘home’ topics he was studying.

 

When Bernard started in Science, it was in the early days of Molecular Biology and

Developmental Biology started to emerge as a new field of investigation. Bernard did his PhD

in Strasbourg (France, LGME, Director: Pf. P. Chambon) using Drosophila melanogaster as a

model organism, focusing his study on the molecular characterization and analysis of the

function of a gene essential to the formation of the mesoderm at gastrulation, the twist gene.

After its cloning (a very long walk in the 80’s) and analysis of its expression, he both sequenced

the twist gene and generated antibodies to visualize its expression. He then studied the

interaction of twist with the maternal transcription factor known to be required for the

formation of ventral domains of the fly embryo, the dorsal gene. He found that the

transcription of twist is directly activated by dorsal and therefore that the transfer of the

maternal information to the zygote involves a cascade of transcriptional activation.

 

Just after getting his PhD, he got a CNRS position (very rare to get it at this step of a

career). Bernard then moved to University of Oregon for his post-doc (under the supervision

of Pr J. Postlethwait, University of Oregon, Eugene) to evaluate the potentialities of a novel

and very promising animal model, the zebrafish. Prof P. Chambon had already offered us lab

space at our return to France to start the zebrafish model in his new institute: at the IGBMC

(Strasbourg, France). Everything had to be built (e.g.: cloning genes, getting markers, genetic

tools, developing various protocols for injection, transplants…). Convinced that the zebrafish

model would be the perfect model to study early patterning events, Bernard decided to

approach the question by studying first the establishment of the dorso-ventral axis and then

to elucidate the formation of the antero-posterior axis.

 

As a PI in IGBMC, his major contribution has been to establish that the dorso-ventral

patterning depends on the morphogenetic activity of an heterodimer of bone morphogenetic

proteins (BMP2b/BMP7) regulated by three antagonists Chordin, Noggin1 and Follistatin-like

1b and on the activity of the FGF signaling pathway that restrict BMP gene expression to the

ventral part of the embryo. We found that this FGF activity is negatively regulated by Sprouty2,

Sprouty 4 as well as by Sef (Interleukin 17 receptor D).

 

A second major contribution to the field of early zebrafish development was to

demonstrate that the Nodal signaling pathway is responsible for the graded establishment of

cell fates along the antero-posterior axis of the zebrafish embryo and to identify Antivin/Lefty

to be a competitive inhibitor of Nodal that limits its activity. Bernard also reexamined the

concept of dorsal/Spemann Organizer in the organization of the embryo. We discovered that

the organizing properties are not restricted to the dorsal margin of the embryo as previously

described but instead are distributed all along the embryonic margin. At the molecular level,

we found that these organizing activities depend on the ratio of activity of two morphogenetic

gradients, BMP and Nodal. We demonstrated that two opposing gradients of BMP and Nodal

are sufficient, both in vivo and in vitro, to instruct uncommitted cells of the zebrafish blastula

animal pole and to become organized into a well-developed embryo.

 

Based on his very sharp in situ and intact embryo morphology, Bernard realized that

maternal Wnt8a mRNA was deposited at the vegetal pole of the embryo. From there, we

identified that the maternal Wnt8a mRNA was the zebrafish dorsal determinant. The lab

showed that this mRNA is transported from the vegetal pole to the blastomeres on one side

of the embryo that becomes the dorsal side. We also demonstrated that the extent of Wnt8a

domain of activity at blastula stage is restricted to the dorsal margin by the activity of two

maternally provided Wnt antagonists, Sfrp1a and Frzb.

 

Finally, we also discovered a novel mechanism for the regulation of the transcriptional

outcome of the canonical Wnt/β-catenin signaling pathway that involves a modulation of the

activity of the TCF corepressors Groucho/TLE through their sequestration by interaction with

the transcription factors Lbx2.

 

Even very successful (number of papers, high impact journals, awards, grants), Bernard

wanted to get out of his comfort zone, in being exposed to other ways of approaching

questions in Science and to interact with people having a different background than his own.

The obvious choice for us was to go back to the US, and we moved in 2007 to be relocated in

the School of Medicine, University of Virginia, Charlottesville.

 

The main adventures there were of 2 folds: leave the early patterning questions to get

interested in Left-Right asymmetry with a transcription angle and second, build a mammalian

embryo-mimetic system using a new model system for us (mouse embryonic stem cells)

instructed with spatially localized morphogen activity gradients.

 

We found that the transcription factors and transcription cofactors mediating or

regulating the transcriptional outcome of the Hippo pathway control the development and

differentiation of the progenitors of the Left-Right organizer and therefore left-Right

asymmetry. These factors regulate all transcription factors known to be required for the

function of the organizer as well as the expression of essential ligands and receptors of major

signaling pathways (Nodal, FGF, non-canonical Wnt and Notch) previously shown to be

essential for the formation of the Left-Right organizer. Finally, one of the transcription

cofactor Vgll4l regulates spatially and temporally the expression of de novo DNA

methyltransferases and methylbinding proteins: writers and readers of DNA methylation

marks. This was the first example demonstrated in a living and wild-type embryo of a

regulation of epigenesis through the transcriptional control of DNA modifying enzymes.

 

Based on the discovery we made showing that two opposing gradients of BMP and

Nodal are sufficient, both in vivo and in vitro, to instruct uncommitted cells of the zebrafish

blastula animal pole and to become organized into a well-developed embryo, Bernard had the

excitement to explore inducing embryonic development from aggregates of mouse embryonic

stem cells. We have been able to induce in vitro formation of the 3 germ layers through a

process of gastrulation and their differentiation in various tissue and organ primordia,

mimicking the development of the mouse embryo up to mid-gestation. Moreover, we

observed formation of a notochord, vasculature and a neural plate folding to form a neural

tube. This was the last paper Bernard published. In between heavy cycles of treatments, he

insisted to mount all the figures himself. You can easily recognize Bernard’s style. Science was

Art for him too.

 

More than anything, he loved interacting with other scientists and developed many

collaborations, most of them within the Zebrafish community (e.g.: working on novel

primordial germ cell specific genes, the origin of embryonic macrophages, left-right

asymmetry of the brain, made a library of expression pattern of the whole family of zebrafish

nuclear receptors, studied the family of fatty acid binding proteins, Na/K ATPases and

adenosine and dopamine receptors, or a family of blood markers). He had the crazy idea and

the gut that took every evening of his life during years to build an in situ database, as a

resource for the scientific community. This database is still heavily used and he (I) still get

many requests for sending clones or asking for advices. Bernard provided the scientific

community with more than 50,000 pictures.

 

Because of his health condition and heavy care plan, we decided to get retired 09.01.

2021 and closed the zebrafish lab. Bernard was excited by the idea of going back to the bench

early January 2022 to perform experiments as a volunteer scientist and to continue on the

mouse stem cell project focusing on the formation and development of the brain in

embryoids. This did/will not happen.

 

Altogether, Bernard could be proud of what he achieved. He answered most of the

questions he raised, used a mix of technologies to answer them (e.g.: molecular biology,

genetics, genomics, imaging, dissections, transplants, injections…). He published a number of

studies in prestigious journals and would always want to publish when he would have a

complete story to tell, the best possibly documented.

 

He was a great mentor and conveyed his passion for Science and Philosophy. Students

and post-doctoral fellows he trained took with them his optimism and hard worker attitude.

 

Marie & Agathe were with me the last weeks of Bernard’s life. This was very special.

I miss him so much.

Christine

christhisse@virginia.edu