Profile of Claude Desplan

“I have been in science for four decades and my enthusiasm is still as fresh as on the first day,” says Claude Desplan, the New York University (NYU) biology and neural science Silver professor, who in 2018 was elected as a member of the National Academy of Sciences. Focusing on Drosophila, among other model organisms, Desplan and his team have made significant contributions to the fields of molecular biology, genetics, developmental neurobiology, and electrophysiology. They have provided insights on body axis formation, the generation of neural diversity, the molecular mechanisms involved in retinal and optic lobe development, and the neural circuits underlying motion detection. Using evolutionary developmental biology, or “evo-devo,” approaches, they have elucidated how sensory systems in various organisms adapt to different ecological conditions. Desplan’s Inaugural Article (1) reviews his laboratory’s work on Drosophila over the past decade and describes neural development principles predicted to apply to most organisms, including mammals.

Claude Desplan. Image credit: Danielle Desplan (photographer).

Global Perspective

Born in Algeria in 1953, Desplan was raised with an appreciation of multiple cultures. His mother's family settled in Algeria in the 19th century. Desplan says his mother, age 91, is one of the world’s oldest yoga instructors. Desplan’s father worked in law, as did many of his relatives, yet Desplan forged his own career path. He says, “I wanted to be a surgeon, but there was no good rationale for it.”

When Desplan was 9 years old his family moved to France. There, he drew inspiration from his ninth-grade science teacher, whom he knew as Ms. Joschau. Desplan says, “Even though she was teaching geology at the time, I became interested in the natural sciences and decided to pursue a career in research.” At age 15 he met another woman who influenced his life. “I met Danielle,” says Desplan, “an acclaimed artist who is now my wife, when we were in middle school, and we have been together ever since. She continues to inspire me.” Their family includes their twin children.

Research on Hormones, Calcium Binding

Desplan attended the prestigious École Normale Supérieure of Saint Cloud near Paris, where he obtained a teaching degree in biochemistry in 1975. He worked as a teaching assistant at the Université Paris VII while pursuing a doctorate under the direction of biochemist Moshen Moukhtar. Their collaboration led to an early achievement for Desplan: development of a radioimmunoassay for the human parathyroid hormone (2).

After earning his doctorate in 1979, Desplan stayed at the university for a Doctor of Science degree in molecular biology. With Moukhtar and colleague Monique Thomasset, he studied calcium regulation. They cloned the gene for a calcium-binding protein (3), and Desplan, Thomasset, and colleagues helped determine the structure and function of the calbindin protein (4).

Pioneering Work on Transcription

Desplan admired University of California, San Francisco (UCSF) developmental biologist Patrick O’Farrell. On a whim, he traveled to San Francisco and tracked down O’Farrell, who later hired Desplan as a postdoctoral associate in molecular genetics at UCSF. O’Farrell’s laboratory was then working on transcription factors in the early-stage Drosophila embryo after having recently cloned the homeobox gene Engrailed. (Homeobox genes contain a short DNA sequence that encodes a homeodomain, which is a highly conserved autonomously folding functional unit of a protein.) Desplan says, “When homeobox genes were discovered and shown to be conserved, both in sequence and function, they collectively became ‘The Rosetta Stone’ of developmental biology.”

Desplan demonstrated that the homeodomain is the DNA-binding motif within this class of transcription factors (5). Studying the Drosophila homeodomain protein Engrailed, he determined the DNA sequence bound by this protein motif (6). He says, “This work started my career in the field of development to understand the specificity of homeoproteins.”

Structure and Function of Homeoproteins

In 1987, Desplan moved to New York City to join The Rockefeller University’s faculty as an HHMI assistant professor and investigator. He advanced to associate professor and HHMI investigator. In 1999, Desplan assumed his present title at NYU, while also becoming director of NYU’s Center for Developmental Genetics and an affiliate professor of biology at NYU Abu Dhabi, where part of his laboratory is located. There, he works with Khaled Amiri of United Arab Emirates University to genetically alter the red palm weevil to help prevent its destruction of date palms, the region’s major crop trees.

Continuing his research on homeoproteins, Desplan and colleagues showed how the protein Hunchback is required for the homeodomain protein Bicoid to execute all of its functions in Drosophila embryo anterior patterning (7). They revealed that the gene Bicoid in flies replaces a series of genes present in other insects (8). Desplan also became interested in the PAX family of homeoproteins, and he and his team showed that the PAX proteins Paired and PAX6 contain two DNA-binding domains, a Paired domain as well as a homeodomain that can act synergistically (9). With structural biologists Carl Pabo and John Kuriyan, he determined the structure of these two domains bound to DNA (10, 11).

Retinal Development and Stochasticity

Desplan’s research on PAX6 led to his laboratory’s interest in eye development since his team discovered that retinal rhodopsin genes share a common PAX6 homeodomain-binding site (12). They further determined that a special class of photoreceptors develops to form a polarized light-based “compass” (13). The system enables insects to detect the vector of light polarization for navigation.

In 2006, Desplan and colleagues showed how stochastic decisions contribute to the diversification of photoreceptors that create the retinal mosaic for color vision (14). He says, “This marked my entry into the field of stochasticity.” Applying the then newly developed CRISPR technology to evo-devo research, Desplan and his team later revealed how butterfly color photoreceptor cells also make stochastic choices that lead to improved color vision (15).

Optic Lobe Development, Generation of Neural Diversity

To better understand the generation of neural diversity, Desplan focused on the optic lobes, which, through the action of 60,000 neurons, drive the sophisticated visual function of Drosophila. He and his team provided evidence for temporal patterning, whereby a series of transcription factors are sequentially expressed in neural stem cells that produce different neurons at each division (16). Illuminating the process further, they showed that a combination of regional and temporal neuronal specification of medulla neural stem cells generates neural diversity (17).

Single-cell transcriptomics aided Desplan’s investigations on the generation of neural diversity. Conducting research both at the NYU Center for Genomics and NYU Abu Dhabi, Desplan and colleagues used the technique and revealed that distinct molecular mechanisms can generate the same features, such as expression of the same neurotransmitter, in different neurons (18).

Mechanisms Underlying Motion Detection

To uncover insights into nervous system development, Desplan and his team have also analyzed the function of medulla neurons that participate in the neural network for motion detection. They discovered the neural implementation of a longstanding model, the Hassenstein–Reichardt correlator, which relies on differential temporal filtering of two spatially separated input channels, delaying one input signal with respect to the other (19).

Desplan and colleagues also discovered that motion-detecting T4 and T5 neurons are produced by the same stem cell at the same time (20). The neurons synchronously project to the same position in the brain corresponding to a specific point in visual space, he explains, such that the organization of neuronal projections results directly from neuronal birth order.

They additionally found an unexpected source for brain development: glia, which are a collection of nonneuronal cells (21). Desplan and colleagues revealed that glia relay cues from the retina to the brain to make cells in the latter become neurons. He says, “By acting as a signaling intermediary, glia exert precise control over not only when and where a neuron is born, but also the type of neuron it will develop into.”

Genetics of Ants

“I always have a little zoo in my lab,” Desplan says, referring to Drosophila and other organisms his team studies. In 2015, he began a collaboration with biochemist Danny Reinberg in developing ant models. Their first project involved creating a mutant of the ant Harpegnathos saltator that was unable to detect pheromones (22). As a model to enable in-depth functional analysis of genes that regulate social interaction in a complex society, the ant may help to identify genetic mechanisms involved in social communication in other species, including humans.

For a more recent study, Desplan and colleagues investigated changes in the ant’s social behavior and accompanying changes in gene expression during the transformation of workers into pseudoqueens when the real queen dies (23). They found that a lack of queen pheromones perceived by the olfactory system affects brain neurohormonal factors that, in turn, leads to altered social behavior and hormone-mediated physiological changes in other parts of the body.

Formulating Concepts of Neural Development

In 2020, Desplan and his team created a “developmental atlas” of gene expression in developing neurons using gene sequencing and machine learning to categorize most of the 200 neurons in the Drosophila optic lobes (24). He says, “This is a huge compendium of the changes in transcription in developing neurons.” It was made possible by his laboratory’s years of data on this model organism that enabled a comparison of cells in the brains of adult flies and an exploration of differences during development.

Work on both the atlas and his Inaugural Article (1) involved molecular genetics and single-cell mRNA sequencing, a technique that allowed them to capture and sequence mRNA from more than 250,000 single cells. Compiling this recent data with Drosophila study findings from the past decade, Desplan and coauthor Jennifer Malin defined general concepts of neural development, such as how temporal transcription factors specify the production of discrete cell types. The authors believe that the basic principles underlying the Drosophila visual system are broadly applicable to mammals. Desplan is now investigating how neuronal diversity at the level of neural stem cells is implemented and how connectivity is established.

Mission as Educator and Mentor

In addition to maintaining an active research program, Desplan is a dedicated educator who has trained at least 30 doctoral students and 50 postdoctoral associates, many of whom hold academic positions throughout the world. He was recognized for his mentorship in 2020 when he received the Edwin G. Conklin Medal from the Society for Developmental Biology.

Previously, Desplan received NYU’s “Golden Dozen” Teaching Award and the French Academy of Sciences’ Grand Prix Charles-Mayer. In 2017, he was named one of the eight “coolest professors at NYU” (25). Desplan says, “I try to be inspiring and to impart my love of science to all of my students, from sophomores and juniors to postdocs. While I think globally, I act locally to do what I can to empower the next generation of scientists.”