On February 28th 2023, Juan Modolell passed away at his home in Madrid aged 85, leaving the developmental biology community bereaved of a pioneer in neural pattern formation. He was an extraordinary scientist who made seminal discoveries in two unrelated fields of work – Escherichia coli protein biosynthesis and Drosophila melanogaster developmental biology. All of us who had the privilege of knowing Juan will remember a brilliant, generous and forward-thinking scientist, who did not stop inventing himself and who left wonderful advice to future generations of young scientists: ‘Have fun doing science and do not be afraid of changing topics, because it is a rejuvenating experience that helps to keep the passion for science.’Juan Modolell was born in Barcelona, Spain, in 1937. From childhood, he was passionate about animals but, unlike most children, he preferred insects to furred animals, being fond of observing, collecting and photographing butterflies and beetles (a hobby that he perfected during his life). Unsurprisingly, he obtained a bachelor's degree in Biological Sciences at the University of Barcelona, Spain, in 1959 but, reasoning that unless he devoted himself to teaching, biology would not serve him to earn his livelihood, he obtained a second degree in Biochemistry at the University of La Laguna (1962) in the Canary Islands, where his family had moved following his father's job as a chemist at an oil refinery. Although his original plan was to become an industrial chemist, he finally enrolled in research at the laboratory of R. O. Moore at the Department of Biochemistry, Ohio State University, USA, characterising an ATPase from rat liver adipose tissue and obtaining a PhD in Biochemistry in 1966. From there, he moved to the laboratory of Bernard Davis, a prominent figure in microbiology at Harvard Medical School (USA), and changed his research topic to the study of the inhibition of E. coli protein biosynthesis by the antibiotic streptomycin (Modolell and Davis, 1969). Juan kept very pleasant memories of this scientifically successful period in Boston, accompanied by his beloved wife Rosa María and their eldest daughter Inés.He came back to Madrid, Spain, in 1970 to join the laboratory of the microbiologist David Vázquez, obtained a second PhD degree (in Chemistry, from the Universidad Complutense de Madrid in 1971), and soon became a staff member of the Spanish National Research Council (CSIC). His work helped to decipher the interaction mechanisms of aminoacyl-tRNA and the elongation factors EF-G and EF-Tu with the ribosome, determined the stoichiometry of ribosomal translocation (Modolell et al., 1973) and revealed the mode of action of several antibiotics that specifically inhibit bacterial protein synthesis.In 1979, Juan was an established researcher in the field of protein biosynthesis when, due to his inclination for addressing developmental problems, he decided to join the emerging community of researchers trying to decipher the molecular basis of development using a combination of genetics and molecular biology. He contacted Antonio García-Bellido, also working at the Centro de Biología Molecular Severo Ochoa, to seek advice on which developmental problem would be best addressed at the molecular level. Antonio was clear, suggesting that Juan work (if he was ambitious enough) on the relevant question of pattern formation (that is, the generation of constant distributions of cell types in a developing tissue or organism), focusing on the molecular analysis of the achaete-scute complex (AS-C).The cuticle of D. melanogaster adults is covered by chaetae, sensory organs (SOs) that develop in a stereotyped pattern, appearing in the same number and at the same positions in all wild-type individuals. Interestingly, some of the chaetae are missing in fly mutants for the achaete (ac) or scute (sc) genes of the AS-C at allele-specific positions. Furthermore, flies carrying Hairy wing mutations, which map at the AS-C, display ectopic SOs. These phenotypes suggested that AS-C genes play a key role in SO patterning (García-Bellido, 1979). After a brilliant presentation by Antonio on all the subtleties and unknowns of the system, Juan took Antonio's advice and was determined to give a definitive turn to his scientific career.To clone AS-C, a technically challenging project in the early 1980s, and much more so in Spain, Juan returned to Boston with his family, which by then had increased to three daughters. There, at Harvard University and with the help of Welcome Bender, Mat Meselson and Victor Corces, he managed to clone a genomic fragment of the AS-C (see Modolell et al., 1983 for details) and returned to Madrid in the summer of 1981. That clone was used as the starting point for a chromosomal walk within the AS-C performed by Modolell's group (initially, a small team of five women including two young predoctoral students, M.R-G. and Laura Carramolino), which led to the cloning of more than 90 kb of contiguous DNA of the AS-C, as well as the mapping of the molecular lesions associated with most of the available ac and sc mutations within the cloned genomic DNA, and the identification of the transcription units of the three components of the AS-C known at that time: ac, sc and lethal of scute. This was the first report of cloning a developmental gene complex (Campuzano et al., 1985, 1986; Carramolino et al., 1982).Although these were very relevant observations, Juan's main concern was to determine the role of the AS-C in the patterning of the adult SOs. Each chaeta is formed by several cells that derive from a SO precursor cell (SOP). Thanks to using one enhancer trap line that accumulates β-galactosidase in the SOPs, it was possible to determine the strict correlation between the position of SOPs in the wing imaginal disc (the precursor of the notum and wing of the adult fly) and that of the adult fly chaetae. Therefore, the problem of how the pattern of SOs was generated shifted to understanding how the pattern of SOPs was established in the wing disc. Modolell's team and others (Cubas et al., 1991; Romani et al., 1989; Skeath and Carroll, 1991) demonstrated that ac and sc are co-expressed in clusters of cells in the wing disc and that SOPs showed an enhanced accumulation of Ac and Sc proteins. Furthermore, ectopic expression of ac or sc led to ectopic SOs (Balcells et al., 1988; Rodríguez et al., 1990). These results, combined with the involvement of the AS-C in the development of the embryonic central nervous system, described by Jiménez and Campos-Ortega (1979), and the in situ hybridization data to visualize the embryonic expression of AS-C genes (Cabrera et al., 1987; Romani et al., 1987), indicated that the AS-C proteins endow ectodermal cells with the ability to become neural precursors (either SOPs or neuroblasts). Accordingly, Juan and Alain Ghysen coined the name ‘proneural’ for these genes, and the clusters of cells expressing proneural genes were called ‘proneural clusters’ (Ghysen and Dambly-Chaudiere, 1989; Romani et al., 1989).The key role of ac-sc in the patterning of the notum external SOs thus relies on their spatially and temporally restricted pattern of expression in the wing disc. Thus, the next relevant question was to understand how this expression is controlled. Modolell's group predicted the existence of cis-regulatory elements (enhancers; first proposed for a developmental gene complex) in the non-transcribed genomic DNA of the AS-C that would drive its expression at precise positions of the wing disc (Ruiz-Gómez and Modolell, 1987). Juan's team demonstrated that these enhancers were present, and an additional enhancer was required to reinforce ac and sc expression in neural precursors, as well as the use of shared enhancers that accounted for the identical expression patterns of ac and sc (Culí and Modolell, 1998; Gómez-Skarmeta et al., 1995; Martínez and Modolell, 1991).The next logical aim was to characterise the genes and signalling pathways that act through those enhancers to control ac/sc expression; the so-called ‘prepattern genes’, based on ideas envisaged by C. Stern 70 years ago (Stern, 1954; reviewed by Ghysen and Dambly-Chaudiere, 1989; Gómez-Skarmeta et al., 2003). The prepattern model predicted that prepattern genes were expressed in the wing disc in domains partially overlapping the proneural clusters. AS-C would act as an integrating device, reading prepattern information and, consequently, allowing ac/sc transcription to take place only in clusters of cells harbouring the adequate combination of prepattern proteins. Several prepattern genes were identified in Juan's lab including pannier, tailup, charlatan and those forming the Iroquois complex (Leyns et al., 1996; García-García et al., 1999; Gómez-Skarmeta et al., 1996; de Navascués and Modolell, 2010; Escudero et al., 2005). Similarly, it was determined that the molecular mechanisms that led to the specific accumulation of Ac and Sc proteins in SOPs involved the action of the proneural proteins, Notch and epidermal growth factor receptor signalling pathways on SOP-dedicated enhances (Culí and Modolell, 1998; Culí et al., 2001).Surprisingly, data from Juan's laboratory showed that transient, generalised expression of sc in wing discs devoid of the endogenous Ac and Sc proteins led to the development of some chaetae at the standard positions (Rodríguez et al., 1990). These findings suggested that SO patterning relies on topological informational in addition to the spatially restricted distribution of Ac/Sc proteins. Again, Juan's team provided a molecular explanation to this puzzling observation that relies on the activity of extra macrochaetae (emc), loss-of-function of which causes the development of extra chaetae. AS-C genes encode transcription factors of the basic-helix-loop-helix (bHLH) family that form heterodimers with the bHLH protein Daughterless (Da) and bind to the DNA through their basic region. Cloning emc (Garrell and Modolell, 1990; Ellis et al., 1990) demonstrated that it encodes an HLH protein devoid of the basic DNA-interacting domain. Emc competes with Da in binding to Ac or Sc, forming Emc/Ac or Emc/Sc dimers unable to bind to DNA and effectively sequestering Ac/Sc proteins. Furthermore, Emc distribution provided positional information in the wing disc, because SOPs appear within proneural clusters in regions with minimal levels of emc expression (Cubas and Modolell, 1992; Van Doren et al., 1992).These discoveries from Juan's group were paradigmatic because they established how hierarchical gene activity generates morphological patterns. Furthermore, they facilitated the identification of proneural genes in other invertebrates and vertebrates, thus demonstrating the universality of the proneural function and marking the beginning of our knowledge of nervous system development (Gómez-Skarmeta et al., 2003). After this pioneering work on pattern formation, Juan continued making important contributions to our understating of other developmental processes in Drosophila. It is common in development for a single protein to control different processes and this is indeed the case for the Iroquois-complex homeodomain proteins. After their discovery as components of the prepattern, Iroquois genes were reported to be involved in the specification of the presumptive notum region of the wing disc and of the dorsal compartment of the eye disc, just to mention two of their functions (Cavodeassi et al., 2000; Diez del Corral et al., 1999; Villa-Cuesta et al., 2007). Iroquois genes are evolutionarily conserved and, from there, Juan and his group embarked on the analysis of the role of these genes in Xenopus development demonstrating that, similar to their Drosophila counterparts, they control the expression of proneural genes and neural plate specification (reviewed by Cavodeassi et al., 2001). Last, but not least, Juan participated in international initiatives such as the sequencing of the Drosophila genome.Juan was a mentor for several generations of researchers. The members of his laboratory, who he considered his second family, as well as many visiting researchers, benefited from the know-how and the excellent scientific environment of Juan's lab. Many of these researchers presently form an active school and all of them were marked to some extent by Juan's approach to scientific research that combined an elegant experimental design (not devoid of risk), the most rigorous execution of the experiments, exhaustive data analyses and concise writing. Once retired, he continued being an active member of the group providing invaluable advice to all who approached him seeking guidance. We were very fortunate to have him as a colleague and friend and will never forget him.The authors thank the family, friends and collaborators of Juan Modolell for their help in the elaboration of this manuscript.
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