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Jean-François Brunet

Development and evolution of neural circuits

A long line of biologists, from the physiologist Xavier Bichat (1771-1802) to the paleontologist Alfred Romer (1894 -1973), have described the vertebrate body in general, and its nervous system in particular, as made of two parts, one somatic and one visceral, “imperfectly welded onto each other”: the somatic part deals with “external affairs” (i.e. our relation to the environment), the visceral part deals with “internal affairs” (i.e. homeostasis, through the control of respiratory, cardiovascular and digestive functions). In a striking echo of this view, we discovered some years ago that the majority of the constituent neurons of the visceral circuits (sensory neurons of epibranchial ganglia, motor neurons of autonomic ganglia, and several classes of interneurons) share a dedicated transcription factor, Phox2b, a veritable “master gene” of the visceral circuits, which sets them apart from somatic neurons. This ontogenetic unity—which makes visceral reflex circuits, collectively, one organ, and visceral neurons, collectively, one class (or super-class) of neurons—, informs much of our work. We study simultaneously several parts of the visceral circuits, and from several perspectives: embryological, physiological and evolutionary, each line of research contextualized by the others.

From an embryological standpoint, we study the formation of autonomic ganglia (parasympathetic, enteric, pelvic) and of epibranchial (sensory) ganglia. We have shown that parasympathetic ganglia form by aggregation of Schwann cell precursors that migrate along cranial nerves towards the site of ganglion formation and we are currently exploring the molecular underpinning of this phenomenon. We have shown that, in sensory neurons, Phox2b serves as a switch from a somatic identity (e.g. touch receptors) to a visceral one (e.g. baroreceptors or chemoreceptors). We are currently studying several other genetic determinants of these neurons that cooperate with Phox2b. And we are exploring the formation of the mysteriously “mixed” (parasympathetic/sympathetic) pelvic ganglion.

From an evolutionary standpoint, we have shown that the central nervous system of adult tunicates (Ciona intestinalis) — essentially «visceral» creatures that spend their lives fixed on the sea floor, breathing and feeding — harbors homologues of the vertebrate cranial “branchiomotor” neurons, the respiratory motoneurons of fish (thus, cranial motoneurons predate craniates). We have more recently shown that the viscero-somatic duality of sensorimotor circuits is present in mollusks (and thus, predates bilaterians). We are currently searching for respiratory centers in fish that could be compared to those of terrestrial vertebrates.

From a physiopathological standpoint, we have used intersectional genetics in mouse to find the locus of the central chemoreflex (i.e. hyperventilation in response to high CO2), the “Retrotrapezoid nucleus”, a group of interneurons which depend on Phox2b and are the likely culprit in the deadly respiratory symptoms of Congenital Central Hypoventilation Syndrome (CCHS), a human disease caused by mutations in PHOX2B. We are currently exploring the function of a related group of interneurons in the hindbrain. This line of research is made in collaboration with the group of Gilles Fortin in Gif-sur-Yvette.

Dufour, H, Chettouh, Z, Deyts, C, de Rosa, R, Goridis, C, Joly, J.-S
and Brunet, J.-F.
Precraniate origin of cranial motoneurons.
Proc. Nat. Acad. Sci. USA (2006), 103 — 8727-8732.

Dubreuil V., Ramanantsoa N., Trochet D., Vaubourg V., Amiel J.,
Gallego J., Brunet J.-F*., and Goridis G.*
A human mutation in the transcription factor Phox2b causes lack of CO2 chemosensitivity, fatal central apnoea and specific loss of parafacial neurons.
Proc. Nat. Acad. Sci. USA (2008), 105 — 1067-1072. *co-corresponding authors

Nomaksteinsky M., Röttinger E., Dufour HD., Chettouh Z., Lowe CJ.,
Martindale MQ., Brunet J.-F.
Centralization of the Deuterostome Nervous System Predates Chordates.
Curr. Biol. (2009), 19 — 1-6.

Dubreuil V., Thoby-Brisson M., Rallu M., Persson M., Pattyn A.,
Birchmeier C., Brunet J.-F.*, Fortin G.*, Goridis C.*
Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b
mutants targeting retrotrapezoid nucleus neurons.
J. Neurosci. (2009), 29 — 14836-46.*corresponding authors

Coppola E., Rallu M., Richard J., Dufour S., Riethmacher D., Guillemot
F., Goridis C., Brunet J.-F.
Epibranchial ganglia orchestrate the development of the cranial neurogenic crest. Proc. Nat. Acad. Sci. USA (2010), 107 — 2066-2071.

D’Autréaux F, Coppola E, Hirsch MR, Birchmeier C, Brunet JF.
Homeoprotein Phox2b commands a somatic-to-visceral switch in cranial sensory pathways.
Proc. Nat. Acad. Sci. USA (2011) 108 — 20018-23.

Nomaksteinsky M, Kassabov S, Chettouh Z, Stoeklé HC, Bonnaud L, Fortin G, Kandel ER and Brunet JF
Ancient origin of somatic and visceral neurons
BMC Biology (2013), 11:53

Espinosa-Medina I, Outin E, Picard C.A, Chettouh Z, Dymecki S, Consalez G.G, Coppola E, Brunet JF.
Parasympathetic ganglia derive from Schwann cell precursors
Science (2014) 345 : 87-90.

Ruffault, P.-L., D’Autréaux, F., Hayes, J.A., Nomaksteinsky, M., Autran, S., Fujiyama, T., Hoshino, M., Hägglund, M., Kiehn, O., Brunet, J.-F., et al.
The retrotrapezoid nucleus neurons expressing Atoh1 and Phox2b are essential for the respiratory response to CO 2.
eLife. 2015; 4: e07051.

Espinosa-Medina I, Saha O, Boismoreau F, Chettouh Z, Rossi F, Richardson WD, Brunet JF
The sacral autonomic outflow is sympathetic
Science (2016) 354 : 893-897

Espinosa-Medina I, Jevans B, Boismoreau F, Chettouh Z, Enomoto H, Müller T, Birchmeier C, Burns A.J., Brunet JF
Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest
Proc. Nat. Acad. Sci. USA. (2017) 114 : 11980-11985

Espinosa-Medina I, Saha O, Boismoreau F, Brunet JF
The "sacral parasympathetic": ontogeny and anatomy of a myth
Clin. Auton. Res. (2017)