Sympathetic tales: subdivisons of the autonomic nervous system and the impact of developmental studies

Abstract

Remarkable progress in a range of biomedical disciplines has promoted the understanding of the cellular components of the autonomic nervous system and their differentiation during development to a critical level. Characterization of the gene expression fingerprints of individual neurons and identification of the key regulators of autonomic neuron differentiation enables us to comprehend the development of different sets of autonomic neurons. Their individual functional properties emerge as a consequence of differential gene expression initiated by the action of specific developmental regulators. In this review, we delineate the anatomical and physiological observations that led to the subdivision into sympathetic and parasympathetic domains and analyze how the recent molecular insights melt into and challenge the classical description of the autonomic nervous system.

Keywords: Autonomic nervous system; Heart; Parasympathetic; Pelvic ganglion; Postganglionic; Preganglionic; Sacral; Sympathetic; Transcription factor.

Fig. 1

Schematic illustration of the sympathetic neuron subtype differentiation in the mouse. BMP-signaling at the dorsal aorta elicits the expression of a group of transcription factors, including Phox2b, Hand2 and Gata3 [–158, 221] that induce noradrenergic (Th, Dbh) and cholinergic genes (ChAT, VAChT), resulting in a high proportion of cells with a mixed noradrenergic/cholinergic phenotype at E10.5-E11.5 [143, 151]. At birth, the vast majority of postmitotic sympathetic neurons display noradrenergic properties; cholinergic characteristics are observed only in about 5% of sympathetic neurons [80, 151, 222]. Single-cell RNAseq of mature sympathetic neurons from P30 sympathetic ganglia allowed to define 2 subtypes of cholinergic sympathetic neurons (ACh1 and ACh2) (labeled by red cell bodies) and 5 subtypes of noradrenergic sympathetic neurons (NA1–5) (noradrenergic sympathetic neuron subtypes are labeled by different shades of blue) [80]. ACh1 and ACh2 correspond to previously identified sudomotor and periosteum-innervating neurons [85, 153]. NA2 and NA5 have been identified as nippleerector and piloerector sympathetic neurons. Sudomotor, NA2 and NA5 subtypes differentiate during postnatal development from noradrenergic neurons under the influence of target-derived differentiation signals [80, 87]. Vasoconstrictor, secretomotor, motility-regulating sympathetic neurons as well as other subtypes identified by physiological approaches are not yet characterized with respect to their gene expression signature and whether their differentiation is also controlled by target-derived signals

Fig. 2

Transcriptional control of sympathetic neuron development. a Target genes regulated by Phox2b in sympathetic progenitors are detected in the Phox2b-knockout mouse [140]. Solid black arrows indicate complete absence of the indicated target genes in mutant embryos. In addition to the noradrenergic marker genes Th and Dbh (noradrenergic genes labeled by blue boxes), the cholinergic markers ChAT and VAChT (cholinergic genes labeled by red boxes) are not expressed in Phox2b mouse mutants [142]. Phox2b does not control initial expression of Ascl1 (white box). Expression of the transcription factor Hand2, which is required for Th and Dbh expression [223] depends on Phox2b [224]. Expression of Gata3, which increases Th transcript levels also depends on Phox2b [173]. Embryonic overexpression demonstrates that each of the transcription factors Phox2b, Phox2a, Hand2 and Gata3 is able to induce the expression of any of the other factors in progenitor cells [173, 225, 226] (blue stippled arrows). b In differentiated neurons different target genes are regulated by Phox2b as detected in conditional mutant mice deleting Phox2b after initial differentiation [152]. In differentiated sympathetic neurons Phox2b enhances its own expression but is dispensable for Phox2a and Hand2 yet remains required for Gata3 expression. Markers for the cholinergic phenotype as VAChT, Vip and Ret (cholinergic genes labeled by red boxes) appear independent of Phox2b, as well as the generic neuronal marker Tubb3 (generic neuronal genes are indicated by green boxes). On the other hand, peripherin (Prph) and Dbh depend on Phox2b. Hand2 remains required for Th and Dbh expression (noradrenergic genes labeled by blue boxes) in differentiated embryonic sympathetic neurons [149]. Notably, Hand2 elimination in adult sympathetic neurons reveals still another set of target-genes involved in synapse function [147]

Fig. 3

Preganglionic autonomic neurons, key transcription factors in their embryonic development and the classification of autonomic nervous system domains. The figure schematically displays the sympathetic and parasympathetic domains of autonomic preganglionic neurons and provides classical and recent naming proposals for the distinct subdivisions. These are derived primarily from physiological and pharmacological studies (Langley [1] see figure 1), evolutionary comparison within vertebrates (Nilsson [200], see figure 2) and developmental studies of critical regulators of neuronal cell lineage (Brunet and colleagues first presented in Espinosa–Medina et al., [154], see figure 4). The transcription factors responsible for the current renaming proposal from sacral “parasympathetic” to “sympathetic” are depicted above the schematic illustration of consecutive domains of the central nervous system harboring preganglionic autonomic neurons. The expression patterns and function are discussed in the main text and Table 2. The illustration is modified from Osumi and colleagues [227] with the mesencephalon containing the neuronal cell bodies giving rise to preganglionic axons to the IIIrd cranial nerve (N. oculomotorius) and the parasympathetic ciliary ganglion. The schematic illustration of the metencephalon displays rhombomeres 1 to 7 with the neuronal cell bodies giving rise to the visceromotor axons in the VIIth (N. facialis) and Xth (N. vagus) cranial nerves. The source of the Vth (N. trigeminus) and IXth nerve (N. glossopharyngeus) are omitted for simplicity. Within the thoracolumbar sympathetic domain, three different axon trajectories are indicated: leftward orientation indicating the rostral direction of preganglionic axons towards the SCG, rightward orientation towards more caudally located ganglia in the paravertebral sympathetic chains, and downward orientation indicating projection to prevertebral sympathetic ganglia. In the sacral autonomic domain at the right end of the scheme, axon projections indicate nerve fibers not entering the paravertebral sympathetic chain and traversing abdominal space in the N. pelvicus and pudentus