Draft:Filippo Maria Rijli

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Filippo Maria Rijli (born May 2, 1961) is an Italian developmental and molecular neurobiologist recognized for his work on the genetic and epigenetic mechanisms underlying craniofacial development and neuronal circuit assembly in the brain[1][2]. Rijli is the Director of the Laboratory of Developmental Neuroepigenetics[3] at the Friedrich Miescher Institute for Biomedical Research in Basel (Switzerland), and also Professor of Neurobiology[4] at the University of Basel. In 2022, Rijli has been elected Member[5][6] of the Italian Accademia dei Lincei, one the world’s oldest and most prestigious academies of sciences.

Education and Career

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Rijli attended the humanistic secondary school Liceo Classico E. Repetti in Carrara (Italy). He then earned a Master's degree in Biological Sciences (1985) with honors (summa cum laude) from the University of Pisa (Italy), followed by a research stage at the Italian National Agency for New Technologies, Energy, and Sustainable Economic Development ENEA (Italy) at Casaccia (Rome) (1986). As a predoctoral fellow (1987), Rijli joined the National Cancer Institute at the National Institutes of Health (NIH) in Bethesda (MD, USA). After completing mandatory military service in Italy, he earned a PhD (1991) in Developmental and Evolutionary Biology at the University of Pisa, under the mentorship of Giuseppina Barsacchi. Rijli was then awarded an EMBO long-term fellowship to carry out postdoctoral research (1991-1995) with Pierre Chambon at the Laboratory of Molecular Genetics of Eukaryotes (LGME) in Strasbourg (France). Between 1996 and 2007, Rijli was a Group Leader at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Strasbourg, holding a tenured Research Director position (French: Directeur de Recherche) at the French National Centre for Scientific Research (French: Centre National pour la Recherche Scientifique, CNRS). During this period, he was also a visiting scientist for three weeks in Andrew_Lumsden_(scientist) laboratory at the Centre for Developmental Neurobiology of King's College London (UK). In 1999, Rijli earned a Habilitation to Direct Research (French: Habilitation à Diriger des Recherches, HDR) from Louis Pasteur University in Strasbourg (France), and, in 2008, a second Habilitation with the title of Privatdozent (PD) from the University of Basel, where he was subsequently appointed Professor of Neurobiology[4] in 2012. Since 2008, Rijli is the Director of the Laboratory of Developmental Neuroepigenetics[3] at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland.

Research

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Rijli work combines mouse molecular genetics with developmental neurobiology, focusing on the homeobox genes of the Hox gene family, coding transcription factors, and Polycomb (PRC2) chromatin regulators in neuron development, neural circuit assembly, and craniofacial development. His studies revealed how gene regulation and chromatin dynamics regulate cell identity and developmental plasticity, advancing understanding of the development of the nervous system, craniofacial morphogenesis, and congenital disorders.

1. Hindbrain Development and Neural Circuit Assembly

Rijli showed that Hox genes orchestrate both early and late stages of hindbrain development by conferring neural progenitor cell positional identity, guiding neuronal migration, and shaping axon connectivity.

  • Retinoic acid regulation: Retinoic acid is a metabolite of vitamin A important for development. Deletion of a retinoic acid-responsive regulatory element of the mouse Hoxa1 gene showed its necessity for rhombomere formation in the early hindbrain[7]. Moreover, administration of a non-teratogenic dose of retinoic acid during mouse pregnancy rescued inner ear defects in Hoxa1 mutant fetuses[8]. In collaboration with Licia Selleri (UCSF), Rijli further showed Hox and Pbx gene-dependent regulation of retinoic acid synthesis during hindbrain development[9].
  • Hox function in sensory neurons and circuit formation: The initial observation of persistent Hox gene expression in specific neuronal subpopulations[10] allowed to reveal functions in neuronal migration and topographic axon wiring. In particular, Rijli showed that the sensory centers in the hindbrain—including the somatosensory trigeminal nuclei[11][12], precerebellar nuclei (i.e. providing input to cerebellum)[13][14][15]), vestibular nuclei[16] (in collaboration with Joel Glover, University of Oslo), and auditory nuclei[17]—are intrinsically regionalized by Hox gene activity. These molecular patterns guide the way incoming and outgoing nerve connections are arranged during brain development, generating a spatially ordered map of axon connectivity, or topographic map (neuroanatomy). In particular, Hoxa2 proved essential to build a somatosensory neuronal topographic map of the face in the hindbrain, as shown in whisker-related circuitry[11][12][18].
  • Polycomb and chromatin regulation in neuronal development and circuit formation: The role of Polycomb (in particular of PRC2) was found crucial in trigeminal and precerebellar neurons for maintaining ordered Hox gene expression, enabling long-range migration, neuronal assembly, and neural circuit formation[12][13]. Moreover, Rijli described a novel chromatin signature that controls the neural activity-dependent transcription of immediate early genes in developing somatosensory neurons and circuits[19]. Immediate early genes often encode transcription factors that, in developing neurons, are rapidly activated by sensory inputs. Rijli and his team found that, during development, immediate early genes are embedded in a unique bipartite chromatin state: promoters carry active H3K27ac histone marks, while gene bodies carry repressive Polycomb-dependent H3K27me3 marks. During development, this setup keeps the immediate early genes silent under baseline conditions but allows them to be turned on quickly in response to stimuli. This bipartite chromatin was also found in developing neural crest and embryonic stem cells, suggesting it represents a broader mechanism for fine-tuning how immediate early genes respond to developmental signals[19].

2. Cranial Neural Crest and Craniofacial Development

Rijli research contributed to uncover how cranial neural crest cells acquire positional identity and shape craniofacial structures (reviewed in[20][21][22][23]).

  • Hoxa2 function: As a postdoc with Pierre Chambon, Rijli showed that Hoxa2 inactivation results in homeosis of second pharyngeal arch derivatives, proving its essential role in outer ear, middle ear, and hyoid apparatus development[24]. The discovery that Hoxa2 is both required and sufficient for outer ear formation in mice provided a model for microtia[24][25]. Evolutionary studies revealed conservation of Hoxa2 expression and function across jawless[26] (in collaboration with Shigeru Kuratani, RIKEN (Japan)) and jawed vertebrates[27]. More recently, the Rijli group identified the long-range enhancers controlling Hoxa2 expression in the cranial neural crest cells, essential for its function in craniofacial morphogenesis[28]. These enhancers are located at a very long distance from their target promoter in a neighboring genomic domain[28], or topologically associating domain. Together, these findings contributed to uncover the genetic and regulatory mechanisms underlying how the face and ears form.
  • Developmental plasticity and chromatin regulation: Rijli, along with his team and in collaboration with Michael Stadler (FMI, Basel), showed that cranial neural crest cells retain developmental plasticity via Polycomb-dependent bivalent chromatin, keeping fate-determining transcription factors involved in craniofacial development repressed but poised for activation[29]. As a result, cranial neural crest cells can sense signals from their environment and readily switch on the right transcriptional programs for differentiation at the right time and place. This ensures normal development of craniofacial structures and the assembly of a harmonious face. Such a mechanism enables context-dependent activation, ensuring proper craniofacial morphogenesis, and helps explaining how genetic information and epigenetic regulation together shape craniofacial diversity during development and evolution[29][23][30]

In summary, Rijli work elucidates how Hox gene and Polycomb-mediated chromatin regulation coordinate hindbrain development, neural circuit formation, and craniofacial development. These insights link chromatin dynamics, cell identity, and developmental plasticity, with implications for understanding neural and craniofacial developmental disorders.

Awards and Honors

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References

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  1. ^ "Filippo M. Rijli".
  2. ^ "Rijli | Basel Stem Cell Network | University of Basel".
  3. ^ a b "FMI - Friedrich Miescher Institute for Biomedical Research - Filippo M. Rijli".
  4. ^ a b c "Rijli Filippo | Neuroscience Network | University of Basel".
  5. ^ a b https://www.unibas.ch/en/News-Events/Awards-Honors/Article/Filippo-M.-Rijli-elected-to-Accademia-Nazionale-dei-Lincei.html, https://www.fmi.ch/news-events/articles/news.html?news=555
  6. ^ https://www.lincei.it/en/node/322
  7. ^ Dupé V, Davenne M, Brocard J, Dollé P, Mark M, Dierich A, Chambon P, Rijli FM. In vivo functional analysis of the Hoxa-1 3' retinoic acid response element (3'RARE). Development. 1997 Jan;124(2):399-410. doi:10.1242/dev.124.2.399PMID 9053316
  8. ^ Pasqualetti M, Neun R, Davenne M, Rijli FM. Retinoic acid rescues inner ear defects in Hoxa1 deficient mice. Nature Genetics. 2001 Sep;29(1):34-9. doi:10.1038/ng702 PMID 11528388
  9. ^ Vitobello A, Ferretti E, Lampe X, Vilain N, Ducret S, Ori M, Spetz JF, Selleri L, Rijli FM. Hox and Pbx factors control retinoic acid synthesis during hindbrain segmentation. Developmental Cell. 2011 Apr 19;20(4):469-82. doi:10.1016/j.devcel.2011.03.011 PMID 21497760
  10. ^ Davenne M, Maconochie MK, Neun R, Pattyn A, Chambon P, Krumlauf R, Rijli FM. Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron. 1999 Apr;22(4):677-91. doi:10.1016/s0896-6273(00)80728-x PMID 10230789
  11. ^ a b Oury F, Murakami Y, Renaud JS, Pasqualetti M, Charnay P, Ren SY, Rijli FM. Hoxa2- and rhombomere-dependent development of the mouse facial somatosensory map. Science. 2006 Sep 8;313(5792):1408-13. Epub 2006 Aug 10. doi:10.1126/science.1130042 PMID 16902088
  12. ^ a b c Bechara A, Laumonnerie C, Vilain N, Kratochwil CF, Cankovic V, Maiorano NA, Kirschmann MA, Ducret S, Rijli FM. Hoxa2 Selects Barrelette Neuron Identity and Connectivity in the Mouse Somatosensory Brainstem. Cell Reports. 2015 Oct 27;13(4):783-797. Epub 2015 Oct 17. doi:10.1016/j.celrep.2015.09.031 PMID 26489473
  13. ^ a b Di Meglio T, Kratochwil CF, Vilain N, Loche A, Vitobello A, Yonehara K, Hrycaj SM, Roska B, Peters AH, Eichmann A, Wellik D, Ducret S, Rijli FM. Ezh2 orchestrates topographic migration and connectivity of mouse precerebellar neurons. Science. 2013 Jan 11;339(6116):204-7. doi:10.1126/science.1229326 PMID 23307742 PMC 4824054
  14. ^ Maheshwari U, Kraus D, Vilain N, Holwerda SJB, Cankovic V, Maiorano NA, Kohler H, Satoh D, Sigrist M, Arber S, Kratochwil CF, Di Meglio T, Ducret S, Rijli FM. Postmitotic Hoxa5 Expression Specifies Pontine Neuron Positional Identity and Input Connectivity of Cortical Afferent Subsets. Cell Reports 2020 Jun 16;31(11):107767. doi:10.1016/j.celrep.2020.107767 PMID 32553152
  15. ^ Geisen MJ, Di Meglio T, Pasqualetti M, Ducret S, Brunet JF, Chedotal A, Rijli FM. Hox paralog group 2 genes control the migration of mouse pontine neurons through slit-robo signaling. PLoS Biology. 2008 Jun 10;6(6):e142. doi:10.1371/journal.pbio.0060142 PMID 18547144 PMC 2422855
  16. ^ Pasqualetti M, Díaz C, Renaud JS, Rijli FM, Glover JC. Fate-mapping the mammalian hindbrain: segmental origins of vestibular projection neurons assessed using rhombomere-specific Hoxa2 enhancer elements in the mouse embryo. Journal of Neuroscience. 2007 Sep 5;27(36):9670-81. doi:10.1523/JNEUROSCI.2189-07.2007 PMID 17804628 PMC 6672974
  17. ^ Karmakar K, Narita Y, Fadok J, Ducret S, Loche A, Kitazawa T, Genoud C, Di Meglio T, Thierry R, Bacelo J, Lüthi A, Rijli FM. Hox2 Genes Are Required for Tonotopic Map Precision and Sound Discrimination in the Mouse Auditory Brainstem. Cell Reports 2017 Jan 3;18(1):185-197. doi:10.1016/j.celrep.2016.12.021 PMID 28052248
  18. ^ Erzurumlu RS, Murakami Y, Rijli FM. Mapping the face in the somatosensory brainstem. Nature Reviews Neuroscience 2010 Apr;11(4):252-63. Epub 2010 Feb 24. doi:10.1038/nrn2804 PMID 20179712 PMC 3545448
  19. ^ a b Kitazawa T, Machlab D, Joshi O, Maiorano N, Kohler H, Ducret S, Kessler S, Gezelius H, Soneson C, Papasaikas P, López-Bendito G, Stadler MB, Rijli FM. A unique bipartite Polycomb signature regulates stimulus-response transcription during development. Nature Genetics 2021 Mar;53(3):379-391. Epub 2021 Feb 18. doi:10.1038/s41588-021-00789-z PMID 33603234 PMC 7610396
  20. ^ Pasqualetti M, Rijli FM. Developmental biology: the plastic face. Nature. 2002 Apr 4;416(6880):493-4. doi:10.1038/416493aPMID 11932730
  21. ^ Santagati F, Rijli FM. Cranial neural crest and the building of the vertebrate head. Nature Reviews Neuroscience. 2003 Oct;4(10):806-18. doi:10.1038/nrn1221 PMID 14523380
  22. ^ Minoux M, Rijli FM. Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development. Development. 2010 Aug;137(16):2605-21. doi:10.1242/dev.040048 PMID 20663816
  23. ^ a b Selleri L, Rijli FM. Shaping faces: genetic and epigenetic control of craniofacial morphogenesis. Nature Reviews Genetics. 2023 Sep;24(9):610-626. Epub 2023 Apr 24. doi:10.1038/s41576-023-00594-w PMID 37095271
  24. ^ a b Rijli FM, Mark M, Lakkaraju S, Dierich A, Dollé P, Chambon P. A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene. Cell. 1993 Dec 31;75(7):1333-49. doi:10.1016/0092-8674(93)90620-6 PMID 7903601
  25. ^ Minoux M, Kratochwil CF, Ducret S, Amin S, Kitazawa T, Kurihara H, Bobola N, Vilain N, Rijli FM. Mouse Hoxa2 mutations provides a model for microtia and auricle duplication. Development. 2013 Nov;140(21):4386-97. Epub 2013 Sep 25. doi:10.1242/dev.098046 PMID 24067355
  26. ^ Takio Y, Pasqualetti M, Kuraku S, Hirano S, Rijli FM, Kuratani S. Evolutionary biology: lamprey Hox genes and the evolution of jaws. Nature. 2004 May 20;429(6989):1 p following 262. doi:10.1038/nature02616 PMID 15154395
  27. ^ Pasqualetti M, Ori M, Nardi I, Rijli FM. Ectopic Hoxa2 induction after neural crest migration results in homeosis of jaw elements in Xenopus. Development. 2000 Dec;127(24):5367-78. doi:10.1242/dev.127.24.5367 PMID 11076758
  28. ^ a b Kessler S, Minoux M, Joshi O, Ben Zouari Y, Ducret S, Ross F, Vilain N, Salvi A, Wolff J, Kohler H, Stadler MB, Rijli FM. A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest. Nature Communications 2023 Jun 5;14(1):3242. doi:10.1038/s41467-023-38953-0PMID 37277355 PMC 10241789
  29. ^ a b Minoux M, Holwerda S, Vitobello A, Kitazawa T, Kohler H, Stadler MB, Rijli FM. Gene bivalency at Polycomb domains regulates cranial neural crest positional identity. Science. 2017 Mar 31;355(6332):eaal2913. doi:10.1126/science.aal2913 PMID 28360266
  30. ^ "The Epigenetics Behind Unique Human Faces". 11 July 2017.
  31. ^ "2026 Craniofacial Morphogenesis and Tissue Regeneration Conference GRC".
  32. ^ "NEUcrest | Team > SAB".
  33. ^ https://www.fmi.ch/news-events/articles/news.html?news=384, https://www.unibas.ch/en/News-Events/News/Uni-Research/Basel-research-project-receives-5.3-million-euros.html, https://erc.europa.eu/sites/default/files/document/file/erc_2018_syg_results.pdf
  34. ^ https://journals.openedition.org/annuaire-cdf/226#tocto2n6, https://www.college-de-france.fr/en/person/filippo-rijli, https://salamandre.college-de-france.fr/archives-en-ligne/ead.html?id=FR075CDF_000AP0004_2&c=FR075CDF_000AP0004_2_de-755&qid=sdx_q0
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