Mechanisms and perspectives on differentiation of autonomic neurons

Abstract

Neurons share many features in common but are distinguished by expression of phenotypic characteristics that define their specific function, location, or connectivity. One aspect of neuronal fate determination that has been extensively studied is that of neurotransmitter choice. The generation of diversity of neuronal subtypes within the developing nervous system involves integration of extrinsic and intrinsic instructive cues resulting in the expression of a core set of regulatory molecules. This review focuses on mechanisms of growth and transcription factor regulation in the generation of peripheral neural crest-derived neurons. Although the specification and differentiation of noradrenergic neurons are the focus, I have tried to integrate these into a larger picture providing a general roadmap for development of autonomic neurons. There is a core of DNA binding proteins required for the development of sympathetic, parasympathetic, and enteric neurons, including Phox2 and MASH1, whose specificity is regulated by the recruitment of additional transcriptional regulators in a subtype-specific manner. For noradrenergic neurons, the basic helix-loop-helix DNA binding protein HAND2 (dHAND) appears to serve this function. The studies reviewed here support the notion that neurotransmitter identity is closely linked to other aspects of neurogenesis and reveal a molecular mechanism to coordinate expression of pan-neuronal genes with cell type-specific genes.

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

“…The absence of Hand1-mediated defects might be the result of functional compensation by the related bHLH factor Hand2 within the cranial NCC. This is an established mechanism that functions in both sympathetic neurons and the developing heart (Barbosa et al, 2007;Hendershot et al, 2008;Howard, 2005;McFadden et al, 2005;Vincentz et al, 2012). By contrast, altering Hand1 phosphoregulation alters the ability of Hand1 to interact with potential bHLH dimer partners (Firulli et al, 2003).…”

Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation

“…The evidence for both sympathetic and parasympathetic dysregulation in CCHS follows logically from a basic understanding of the PHOX2B gene role in embryologic development of the sympathetic, parasympathetic, and enteric pathways of the ANS (5,22). We postulate that the demonstrated functional differences in pupillary measures are specific to the ANS efferent pathways.…”

“…Discovery of the CCHS disease-defining gene, pairedlike homeobox 2B (PHOX2B) (2)(3)(4), and appreciation of its role in both embryologic development and regulatory function of the autonomic nervous system (ANS) (5)(6)(7), has broadened the understanding of the CCHS phenotype. The majority of individuals with CCHS are heterozygous for PHOX2B polyalanine repeat expansion mutations (PARMs), with a range of 24-33 alanine bases on the affected allele (20 repeats is normal; normal genotype is 20/20).…”

Trim11 increases expression of dopamine β-hydroxylase gene by interacting with Phox2b

“…NA neurons are found in both the CNS and the PNS. The regulatory mechanism determining the NA neurotransmitter phenotype has been extensively studied, leading to the identification and functional characterization of critical signaling molecules and transcription factors [2,5]. Development of NA neurons in SG of the PNS and locus coeruleus (LC) of the CNS depends on bone morphogenetic proteins (BMPs) that are expressed in dorsal aorta and dorsal neural tube, respectively [2].…”

“…cAMP signaling pathway is also necessary for the induction of NA neurons in rat and avian NCSC culture. Both loss of function and gain of function studies showed that transcription factors, such as Mash1, Phox2b, Phox2a, dHand, and GATA-2/3, work cooperatively to specify NA neuron phenotype [2,[5][6][7][8].…”