Nestin expression defines both glial and neuronal progenitors in postnatal sympathetic ganglia

Abstract

Sympathetic ganglia are primarily composed of noradrenergic neurons and satellite glial cells. Although both cell types originate from neural crest cells, the identities of the progenitor populations at intermediate stages of the differentiation process remain to be established. Here we report the identification in vivo of glial and neuronal progenitor cells in postnatal sympathetic ganglia, using mouse superior cervical ganglia as a model system. There are significant levels of cellular proliferation in mouse superior cervical ganglia during the first 18 days after birth. A majority of the proliferating cells express both nestin and brain lipid-binding protein (BLBP). BrdU fate-tracing experiments demonstrate that these nestin and BLBP double positive cells represent a population of glial progenitors for sympathetic satellite cells. The glial differentiation process is characterized by a marked downregulation of nestin and upregulation of S100, with no significant changes in the levels of BLBP expression. We also identify a small number of proliferating cells that express nestin and tyrosine hydroxylase, a key enzyme of catecholamine biosynthesis that defines sympathetic noradrenergic neurons. Together, these results establish nestin as a common marker for sympathetic neuronal and glial progenitor cells and delineate the cellular basis for the generation and maturation of sympathetic satellite cells. Keywords noradrenergic neurons; satellite cells; superior cervical ganglia; postnatal sympathetic developmentThe sympathetic nervous system is composed of sympathetic ganglia and the adrenal medulla, a specialized sympathetic ganglion containing secretory chromaffin cells. Sympathetic ganglia of mammals are organized into two paravertebral chains that span from cervical to sacral regions, with the ganglia being interconnected with pre-and postganglionic sympathetic nerve fibers. Sympathetic ganglia contain two major cell types, neurons and glial cells. Most mammalian sympathetic neurons use noradrenaline as a neurotransmitter and, thus, are called noradrenergic neurons. These neurons are commonly marked by their expression of tyrosine hydroxylase (TH) that catalyzes the rate-limiting step (Cocchia and Michetti, 1981).It is well established that sympathetic neurons and glia are derived from neural crest cells (Anderson, 1989;LaBonne and Bronner-Fraser, 1998;Le Douarin and Dupin, 1993), a transient, highly migratory population of multipotent stem/progenitor cells. The neural crest can be divided into four regions along the anterior-posterior axis: cranial, vagal, trunk, and lumbosacral neural crest. During sympathetic development, neural crest cells, mainly from the trunk region of the neural crest, migrate ventrally and aggregate adjacent to the dorsal aorta to form the primary sympathetic chain. A subpopulation of the cells then undergo dorsal migration to form the paravertebral sympathetic ganglia where they differentiate into sympathetic neurons and glial cells (Francis and Landis, 1999;Kirby and Gilmore...

MYCN Promotes the Expansion of Phox2B-Positive Neuronal Progenitors to Drive Neuroblastoma Development

“…Most of these nestin ϩ cells express BLBP and differentiate into sympathetic satellite cells. 17 These observations suggest that MYCN may bias nestin ϩ sympathetic progenitors toward a neuronal fate versus a glial fate, thereby contributing to the expansion of Phox2B ϩ neuronal progenitors. This model is consistent with data from several studies.…”

“…It should be pointed out that the majority of nestin ϩ cells in early postnatal sympathetic ganglia of wild-type mice are glial progenitors that express BLBP and differentiate into satellite cells. 17 By contrast, nestin ϩ cells in the hyperplastic lesions expressed either no lineage markers or Phox2B, a neuronal marker. Taken together, these data suggest that MYCN expression not only results in an increase in the number of nestin ϩ sympathetic progenitors, but also biases them toward a neuronal fate.…”

“…Nestin is also expressed in sympathetic glial and neuronal progenitors. 17 Our immunofluorescent staining revealed the presence of three distinct cell populations in hyperplasia: nestin ϩ , Phox2B ϩ , and nestin ϩ Phox2B ϩ cells ( Figure 5A). Given their physical location and the fact that nestin is expressed in neural crest cells that give rise to sympathetic glia and neurons, it appears to be likely that the three cell populations represent distinct stages of sympathetic neurogenesis, with nestin ϩ cells being precursors of the nestin ϩ Phox2B ϩ cells that in turn differentiate into Phox2B ϩ neuronal progenitors.…”

“…Although they have been referred to as "neuroblasts", 9 their identity has not been established. We first wanted to confirm that they are not of glial lineage, in light of our recent finding that the majority of Ki-67 ϩ cells in early postnatal sympathetic ganglia of wild-type mice express BLBP 17 (see also Figure 2A), a marker for glial progenitor cells in the peripheral nervous system including the sympathetic nervous system. 17,18 Immunofluorescent staining revealed that all Ki-67 ϩ hyperplastic cells in TH-MYCN sympathetic ganglia stained negatively for BLBP (Figure 2A), indicating that they are not glial progenitor cells.…”

Hes1 is required for the development of the superior cervical ganglion of sympathetic trunk and the carotid body

“…The superior cervical ganglion (SCG) is then separated from the satellite ganglion at embryonic day (E) 13.5 and becomes localized between cervical levels 1 and 4 (C1 and C4) at E14.5 (Nishino et al, 1999). At these stages of development, the noradrenergic neuronal progenitors are commonly denoted by their expression of TH, whereas the glial progenitors for sympathetic satellite cells are denoted by their expression of brain lipid-binding protein (BLBP; Shi et al, 2008). BLBP belongs to the family of fatty-acid binding protein and is expressed in radial glia in the developing brain.…”