Igor Adameyko

Schwann Cell Precursors from Nerve Innervation Are a Cellular Origin of Melanocytes in Skin

Current opinion holds that pigment cells, melanocytes, are derived from neural crest cells produced at the dorsal neural tube and that migrate under the epidermis to populate all parts of the skin. Here, we identify growing nerves projecting throughout the body as a stem/progenitor niche containing Schwann cell precursors (SCPs) from which large numbers of skin melanocytes originate. SCPs arise as a result of lack of neuronal specification by Hmx1 homeobox gene function in the neural crest ventral migratory pathway. Schwann cell and melanocyte development share signaling molecules with both the glial and melanocyte cell fates intimately linked to nerve contact and regulated in an opposing manner by Neuregulin and soluble signals including insulin-like growth factor and platelet-derived growth factor. These results reveal SCPs as a cellular origin of melanocytes, and have broad implications on the molecular mechanisms regulating skin pigmentation during development, in health and pigmentation disorders.

Glial origin of mesenchymal stem cells in a tooth model system

Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium. It has been thought for decades that the dental mesenchymal stem cells giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue. Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.

Parasympathetic neurons originate from nerve-associated peripheral glial progenitors

Exploiting nervous paths already traveled The parasympathetic nervous system helps regulate the functions of many tissues and organs, including the salivary glands and the esophagus. To do so, it needs to reach throughout the body, connecting central systems to peripheral ones. Dyachuk et al. and Espinosa-Medina et al. explored how these connections are established in mice (see the Perspective by Kalcheim and Rohrer). Progenitor cells that travel along with the developing nerves can give rise to both myelinforming Schwann cells and to parasympathetic neurons. That means the interacting nerves do not have to find each other. Instead, the beginnings of the connections are laid down as the nervous system develops. Science, this issue p. 82, p. 87; see also p. 32 Parasympathetic neurons are born from Schwann cell precursors located in the nerves that carry preganglionic fibers. [Also see Perspective by Kalcheim and Rohrer] The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice—including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia—arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.

Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest

The cellular origin and molecular mechanisms regulating pigmentation of head and neck are largely unknown. Melanocyte specification is controlled by the transcriptional activity of Mitf, but no general logic has emerged to explain how Mitf and progenitor transcriptional activities consolidate melanocyte and progenitor cell fates. We show that cranial melanocytes arise from at least two different cellular sources: initially from nerve-associated Schwann cell precursors (SCPs) and later from a cellular source that is independent of nerves. Unlike the midbrain-hindbrain cluster from which melanoblasts arise independently of nerves, a large center of melanocytes in and around cranial nerves IX-X is derived from SCPs, as shown by genetic cell-lineage tracing and analysis of ErbB3-null mutant mice. Conditional gain- and loss-of-function experiments show genetically that cell fates in the neural crest involve both the SRY transcription factor Sox2 and Mitf, which consolidate an SCP progenitor or melanocyte fate by cross-regulatory interactions. A gradual downregulation of Sox2 in progenitors during development permits the differentiation of both neural crest- and SCP-derived progenitors into melanocytes, and an initial small pool of nerve-associated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.

Retrograde Signaling onto Ret during Motor Nerve Terminal Maturation

Establishment of the neuromuscular synapse requires bidirectional signaling between the nerve and muscle. Although much is known on nerve-released signals onto the muscle, less is known of signals important for presynaptic maturation of the nerve terminal. Our results suggest that the Ret tyrosine kinase receptor transmits a signal in motor neuron synapses that contribute to motor neuron survival and synapse maturation at postnatal stages. Ret is localized specifically to the presynaptic membrane with its ligands, GDNF (glial cell line-derived neurotrophic factor)/NTN (neurturin), expressed in skeletal muscle tissue. Lack of Ret conditionally in cranial motor neurons results in a developmental deficit of maturation and specialization of presynaptic neuromuscular terminals. Regeneration of Ret-deficient adult hypoglossal motor neurons is unperturbed, but despite contact with the unaffected postsynaptic specializations, presynaptic axon terminal maturation is severely compromised in the absence of Ret signaling. Thus, Ret transmits a signal in motor nerve terminals that participate in the organization and maturation of presynaptic specializations during development and during regeneration in the adult.

The retinoic acid inducible Cas-family signaling protein Nedd9 regulates neural crest cell migration by modulating adhesion and actin dynamics.

Cell migration is essential for the development of numerous structures derived from embryonic neural crest cells (NCCs), however the underlying molecular mechanisms are incompletely understood. NCCs migrate long distances in the embryo and contribute to many different cell types, including peripheral neurons, glia and pigment cells. In the present work we report expression of Nedd9, a scaffolding protein within the integrin signaling pathway, in non-lineage-restricted neural crest progenitor cells. In particular, Nedd9 was found to be expressed in the dorsal neural tube at the time of neural crest delamination and in early migrating NCCs. To analyze the role of Nedd9 in neural crest development we performed loss- and gain-of-function experiments and examined the subsequent effects on delamination and migration in vitro and in vivo. Our results demonstrate that loss of Nedd9 activity in chick NCCs perturbs cell spreading and the density of focal complexes and actin filaments, properties known to depend on integrins. Moreover, a siRNA dose-dependent decrease in Nedd9 activity results in a graded reduction of NCCs migratory distance while forced overexpression increases it. Retinoic acid (RA) was found to regulate Nedd9 expression in NCCs. Our results demonstrate in vivo that Nedd9 promotes the migration of NCCs in a graded manner and suggest a role for RA in the control of Nedd9 expression levels.

Glial versus melanocyte cell fate choice: Schwann cell precursors as a cellular origin of melanocytes.

Melanocytes and Schwann cells are derived from the multipotent population of neural crest cells. Although both cell types were thought to be generated through completely distinct pathways and molecular processes, a recent study has revealed that these different cell types are intimately interconnected far beyond previously postulated limits in that they share a common post-neural crest progenitor, i.e. the Schwann cell precursor. This finding raises interesting questions about the lineage relationships of hitherto unrelated cell types such as melanocytes and Schwann cells, and may provide clinical insights into mechanisms of pigmentation disorders and for cancer involving Schwann cells and melanocytes.

Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla

Following the yellow brick road The adrenal glands affect a variety of processes such as stress responses and metabolism. The mature adrenal gland is formed from multiple tissue sources, including cells of neural origin. Furlan et al. traced the origins of these cells. The cells first become Schwann cell precursors and follow along nerves to travel from the dorsal root ganglia of the spine to the adrenal gland. Once there, the cells differentiate into chromaffin cells. The authors used singlecell transcriptomics to reveal the shifts in functional programs during migration, development, and differentiation. Science, this issue p. eaal3753 The adrenal gland is built from cells that travel along highways of nerves. INTRODUCTION Circulating adrenaline can have profound effects on the body’s “inner world,” adjusting levels depending on demand to maintain organ and bodily homeostasis during daily living. In the more extreme fight-or-flight response, the surge of adrenaline is “energizing” through effects on organs and tissues, including increased heart rate and blood glucose levels, and redirecting oxygen and glucose to limb muscles. Chromaffin cells located in the adrenal medulla constitute the main hormonal component of the autonomic nervous system and are the principal source for release of catecholamines, including adrenaline, in the systemic circulation. Understanding the cellular origin and biological processes by which the adrenal medulla is formed during development is needed for mechanistic insights into how the hormonal component of the autonomic nervous system is formed and its relation to the rest of the autonomic nervous system. RATIONALE Adrenergic chromaffin cells in the adrenal medulla are thought to originate from a common sympathoadrenal lineage close to the dorsal aorta, where these cells split in a dorsoventral direction, forming the sympathetic chain and adrenal medulla, respectively. Revisiting this dogma, we examined the cell type origin of chromaffin cells, lineage segregation of sympathoblasts and chromaffin cells, the gene programs driving specification of chromaffin cells from progenitors, and the proliferative dynamics by which the adrenal medulla is formed. RESULTS We found that chromaffin cells of the adrenal medulla are formed from peripheral glia stem cells, termed Schwann cell precursors. Genetic cell lineage tracing revealed that most chromaffin cells arise from Schwann cell precursors, and consistently, genetic ablation of Schwann cell precursors results in marked depletion of chromaffin cells. Genetic ablation of the preganglionic nerve, on which Schwann cell precursors migrate, similarly leads to marked deficiencies of chromaffin cells, and fate-tracing cells unable to differentiate into chromaffin cells reveal an accumulation of glia cells in the region of the adrenal medulla. Experiments reveal that sympathetic and adrenergic lineages diverge at an unexpectedly early stage during embryonic development. Embryonic development of the adrenal medulla relies on recruitment of numerous Schwann cell precursors with limited cell expansion. Thus, the large majority of chromaffin cells arise from Schwann cell precursors migrating on preganglionic nerves innervating the adrenal medulla. Unexpectedly, single-cell RNA sequencing revealed a complex gene-regulatory mechanism during differentiation of Schwann cell precursors to chromaffin cells, whereby Schwann cell precursors enter into a gene expression program unique for a transient cellular state. Subsequently, this gene program and chromaffin cell gene networks suppress glial gene programs, advancing cells into the chromaffin cell identity. CONCLUSION By revisiting development of the adrenergic sympathetic system, we discovered a new cellular origin of this nervous system component. The adrenergic medulla is built from both neural crest cells and Schwann cell precursors, with a major contribution from Schwann cell precursors in rodents. A cellular origin from Schwann cell precursors highlights the importance of peripheral nerves as a stem cell niche and transportation routes for progenitors essential for neuroendocrine development. These results and mechanisms of differentiation through a transient intermediate cell type may also be helpful in advancing our knowledge on neuroblastoma and pheochromocytoma, because these most often arise from the adrenal gland region. Adrenal medulla largely originates from Schwann cell precursors. Overview of adrenal medulla development resulting from lineage tracing and nerve ablation experiments. SCP, Schwann cell precursor; AG, adrenal gland; NT, neural tube; n, notochord; DRG, dorsal root ganglion; IML, intermediolateral column; NCC, neural crest cells; NC, neural crest; DA, dorsal aorta; SRG, suprarenal sympathetic ganglion. Red encodes early NCCs and their derivatives. Blue encodes late neural crest and SCP-derived cell types. Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell–gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.

MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division

The role of MYC proteins in somatic stem and progenitor cells during development is poorly understood. We have taken advantage of a chick in vivo model to examine their role in progenitor cells of the developing neural tube. Our results show that depletion of endogenous MYC in radial glial precursors (RGPs) is incompatible with differentiation and conversely, that overexpression of MYC induces neurogenesis independently of premature or upregulated expression of proneural gene programs. Unexpectedly, the neurogenic function of MYC depends on the integrity of the polarized neural tissue, in contrast to the situation in dissociated RGPs where MYC is mitogenic. Within the polarized RGPs of the neural tube, MYC drives differentiation by inhibiting Notch signaling and by increasing neurogenic cell division, eventually resulting in a depletion of progenitor cells. These results reveal an unexpected role of MYC in the control of stemness versus differentiation of neural stem cells in vivo.

GATA-4:FOG Interactions Regulate Gastric Epithelial Development in the Mouse

Transcription factor GATA‐4 is a key participant in cytodifferentiation of the mouse hindstomach. Here we show that GATA‐4 cooperates with a Friend‐of‐GATA (FOG) cofactor to direct gene expression in this segment of gut. Immunohistochemical staining revealed that GATA‐4 and FOG‐1 are co‐expressed in hindstomach epithelial cells from embryonic days (E) 11.5 to 18.5. The other member of the mammalian FOG family, FOG‐2, was not detected in gastric epithelium. To show that GATA‐4:FOG interactions influence stomach development, we analyzed Gata4ki/ki mice, which express a mutant GATA‐4 that cannot bind FOG cofactors. Sonic Hedgehog, an endoderm‐derived signaling molecule normally down‐regulated in the distal stomach, was over‐expressed in hindstomach epithelium of E11.5 Gata4ki/ki mice, and there was a concomitant decrease in fibroblast growth factor‐10 in adjacent mesenchyme. We conclude that functional interaction between GATA‐4 and a member of the FOG family, presumably FOG‐1, is required for proper epithelial‐mesenchymal signaling in the developing stomach. Developmental Dynamics 234:355–362, 2005.