Neuronal types and their specification dynamics in the autonomic nervous system

The autonomic nervous system is formed by a sympathetic and a parasympathetic division that have complementary roles in the maintenance of body homeostasis. Autonomic neurons, also known as visceral motor neurons, are tonically active and innervate virtually every organ in our body. For instance, cardiac outflow, thermoregulation and even the focusing of our eyes are just some of the plethora of physiological functions under the control of this system. Consequently, perturbation of autonomic nervous system activity can lead to a broad spectrum of disorders collectively known as dysautonomia and other diseases such as hypertension. Neuroblastoma, one of the most common and lethal infancy cancer, arises from defects during the embryonic development of sympathetic neurons. Despite its importance in everyday life and clinical relevance, little is known regarding the molecular mechanisms regulating the birth, differentiation and heterogeneity of the autonomic neurons. This PhD thesis aims at reducing this gap of knowledge.

In paper I, we describe the role of the Homeobox transcription factor HMX1 and receptor signalling in directing neuronal fate during embryogenesis. We propose a new model for sympathetic specification in which mature noradrenergic and cholinergic types emerge from a common progenitor and neuronal identity is established via mechanisms involving active repression of receptors and transcription factors directing alternative cell fates.

In paper II, we take advantage of high-throughput sequencing approaches to explore the heterogeneity of the sympathetic system and describe the existence of seven molecularly distinct cell types. Using a combination of retrograde and lineage tracing approaches, we describe the developmental mechanisms leading to the emergence of two specialized cell types projecting to the pilo (PEM) and nipple (NEM) erector muscles.

In paper III, we show that the parasympathetic nervous system, previously thought to be originated by the Neural Crest Stem Cells (NCSCs) is derived from stem-like Schwann cell precursors (SCPs) intimately associated with the extending cranial nerves during development.

All together, the data collected in this thesis provide new insights into key aspects regulating the origin and development of the autonomic nervous system and provide compelling evidence regarding the existence of specialized cell types regulating specific functions. This knowledge provides new principles on how the autonomic nervous system develops that might help to understand also its pathologies, such as neuroblastoma and dysautonomia.

List of scientific papers

I. Furlan A, Lübke M, Adameyko I, Lallemend F, Ernfors P. The transcription factor Hmx1 and growth factor signaling control sympathetic neurons diversification. EMBO Journal 2013 April; 32(11), 1613-1625
https://doi.org/10.1038/emboj.2013.85

II. Furlan A, La Manno G, Lübke M, Häring M, Abdo H, Hochgerner H, Kupari J, Usoskin D, Airaksinen MS, Oliver G, Linnarsson S and Ernfors P. Visceral motor neuron diversity delineates a cellular basis for nipple- and piloerection muscle control. Nature Neuroscience 2016 October; 19(10), 1331-1340
https://doi.org/10.1038/nn.4376

III. Dyachuk V, Furlan A, Shahidi MK, Giovenco M, Kaukua N, Konstantinidou C, Pachnis V, Memic F, Marklund U, Müller T, Birchmeier C, Fried K, Ernfors P, Adameyko I. Parasympathetic neurons originate from nerve-associated peripheral glial progenitors. Science 2014 July; 345(6192), 82-87
https://doi.org/10.1126/science.1253281