Schwann Cell Precursors Generate the Majority of Chromaffin Cells in Zuckerkandl Organ and Some Sympathetic Neurons in Paraganglia

In humans, neurosecretory chromaffin cells control a number of important bodily functions, including those related to stress response. Chromaffin cells appear as a distinct cell type at the beginning of midgestation and are the main cellular source of adrenalin and noradrenalin released into the blood stream. In mammals, two different chromaffin organs emerge at a close distance to each other, the adrenal gland and Zuckerkandl organ (ZO). These two structures are found in close proximity to the kidneys and dorsal aorta, in a region where paraganglioma, pheochromocytoma and neuroblastoma originate in the majority of clinical cases. Recent studies showed that the chromaffin cells comprising the adrenal medulla are largely derived from nerve-associated multipotent Schwann cell precursors (SCPs) arriving at the adrenal anlage with the preganglionic nerve fibers, whereas the migratory neural crest cells provide only minor contribution. However, the embryonic origin of the ZO, which differs from the adrenal medulla in a number of aspects, has not been studied in detail. The ZO is composed of chromaffin cells in direct contact with the dorsal aorta and the intraperitoneal cavity and disappears through an autophagy-mediated mechanism after birth. In contrast, the adrenal medulla remains throughout the entire life and furthermore, is covered by the adrenal cortex. Using a combination of lineage tracing strategies with nerve- and cell type-specific ablations, we reveal that the ZO is largely SCP-derived and forms in synchrony with progressively increasing innervation. Moreover, the ZO develops hand-in-hand with the adjacent sympathetic ganglia that coalesce around the dorsal aorta. Finally, we were able to provide evidence for a SCP-contribution to a small but significant proportion of sympathetic neurons of the posterior paraganglia. Thus, this cellular source complements the neural crest, which acts as a main source of sympathetic neurons. Our discovery of a nerve-dependent origin of chromaffin cells and some sympathoblasts may help to understand the origin of pheochromocytoma, paraganglioma and neuroblastoma, all of which are currently thought to be derived from the neural crest or committed sympathoadrenal precursors

Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage

Facial shape is the basis for facial recognition and categorization. Facial features reflect the underlying geometry of the skeletal structures. Here, we reveal that cartilaginous nasal capsule (corresponding to upper jaw and face) is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived Sonic Hedgehog (SHH) enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Unexpectedly, the cartilage of the nasal capsule turned out to be important for shaping membranous facial bones during development. This suggests that conserved neurosensory structures could benefit from protection and have evolved signals inducing cranial cartilages encasing them. Experiments with mutant mice revealed that the genomic regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts

Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans

Motor innervation directs the correct development of the mouse sympathetic nervous system

The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the “fight-or-flight response”. Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis

PRDM12 Is Required for Initiation of the Nociceptive Neuron Lineage during Neurogenesis

Summary: The sensation of pain is essential for the preservation of the functional integrity of the body. However, the key molecular regulators necessary for the initiation of the development of pain-sensing neurons have remained largely unknown. Here, we report that, in mice, inactivation of the transcriptional regulator PRDM12, which is essential for pain perception in humans, results in a complete absence of the nociceptive lineage, while proprioceptive and touch-sensitive neurons remain. Mechanistically, our data reveal that PRDM12 is required for initiation of neurogenesis and activation of a cascade of downstream pro-neuronal transcription factors, including NEUROD1, BRN3A, and ISL1, in the nociceptive lineage while it represses alternative fates other than nociceptors in progenitor cells. Our results thus demonstrate that PRDM12 is necessary for the generation of the entire lineage of pain-initiating neurons. : The sensation of pain, temperature, and itch by neurons of the nociceptive lineage is essential for animal survival. Bartesaghi et al. report that the transcriptional regulator PRDM12 is indispensable in neural crest cells (NCCs) for the initiation of the sensory neuronal differentiation program that generates the entire nociceptive lineage. Keywords: neurogenesis, pain, nociceptive neurons, Prdm12, neural crest cell

Serotonin limits generation of chromaffin cells during adrenal organ development

Adrenal glands are the major organs releasing catecholamines and regulating our stress response. The mechanisms balancing generation of adrenergic chromaffin cells and protecting against neuroblastoma tumors are still enigmatic. Here we revealed that serotonin (5HT) controls the numbers of chromaffin cells by acting upon their immediate progenitor "bridge" cells via 5-hydroxytryptamine receptor 3A (HTR3A), and the aggressive HTR3Ahigh human neuroblastoma cell lines reduce proliferation in response to HTR3A-specific agonists. In embryos (in vivo), the physiological increase of 5HT caused a prolongation of the cell cycle in "bridge" progenitors leading to a smaller chromaffin population and changing the balance of hormones and behavioral patterns in adulthood. These behavioral effects and smaller adrenals were mirrored in the progeny of pregnant female mice subjected to experimental stress, suggesting a maternal-fetal link that controls developmental adaptations. Finally, these results corresponded to a size-distribution of adrenals found in wild rodents with different coping strategies

Διερεύνηση του ρόλου της γλοιακής μορφής της πρωτεΐνης TAG-1 στην οργάνωση των εμμύελων ινών στα θηλαστικά

Myelinated fibers are divided in discrete subdomains around the Nav-enriched nodes of Ranvier: the paranodes, where axoglial interactions occur, the juxtaparanodes, where voltage-gated potassium channels (VGKCs) are aggregated, and the internode. The integrity of these domains is crucial for the function of the axon and the propagation of axon potentials along its length. Perinodal changes have been reported in Multiple Sclerosis (MS) with functional consequences for the axon. TAG-1 (Transient Axonal Glycoprotein-1 or Contactin2 – Cntn2), both an axonal and glial protein, is also found enriched at juxtaparanodes and is responsible for the recruitment and maintenance of VGKC and Caspr2 at these sites, while it was also identified as an autoantigen in a subset of MS patients. Furthermore, the protein has been assigned with crucial roles in mediating processes such as migration, fasciculation and maturation in a variety of neuronal subtypes in the developing central nervous system (CNS).In the first part of the study, in an effort to further study its role in myelination, we focused on the role of TAG-1 in demyelination and remyelination in two different murine models. In the first one, the EAE (Experimental Autoimmune Encephalomyelitis) model, we induced demyelination after activation of the immune system directed against a myelin component, driving autoimmunity which results in spinal cord white matter (WM) pathology and associated clinical symptoms. TAG-1 absence resulted in a delay in the development of neurological symptoms, linked to a reduced recruitment of Tregs in the spinal cord. The second model utilizes a toxin (lysophospatidylοcholine - LPC) to induce focal demyelination in the corpus callosum (cc). Following demyelination, TAG-1 affects microglial and astroglial recruitment to the lesioned area, driving also OPC differentiation. Last but not least, in the absence of TAG-1 another mechanism is driven to cluster VGKCs at JXPs during remyelination.In the second part of our study, we report on alterations of the juxtaparanodal proteins TAG-1, Caspr2 and VGKCs in normal appearing white matter (NAWM), perilesion and chronic lesion areas in post-mortem white matter tissue from MS patients compared to control white matter. We show that the molecular organization and maintenance of JXPs is affected in lesions, perilesions and NAWM in chronic MS through protein and mRNA expression as well as immunohistochemistry. The three molecules analyzed were differentially altered. TAG-1 clustering at JXPs was reduced in NAWM; TAG-1 and Caspr2 are diffused in perilesions and absent in lesion areas. VGKCs were no longer enriched at juxtaparanodes either at the NAWM or the perilesion and demyelinated plaques. While the protein levels of the three molecules showed only a tendency of reduction in the plaques, there was a significant upregulation of Caspr2 mRNA in the lesions accompanied by a transcriptional increase of paranodal Caspr, indicating an axonal homeostatic mechanism.Overall, our study points to novel roles of TAG-1 in demyelination and remyelination in mice, such as a pivotal role in driving autoimmunity, microglial and astroglial recruitment, as well as differentiation of oligodendrocyte precursor cells (OPCs) to mature, myelin-producing, oligodendrocytes (OLs). In chronic MS tissue, the comparative analysis of the juxtaparanodal complex revealed for the first time differential alterations of the three components and a juxtaparanodal vulnerability in NAWM, an area of diffuse pathology lacking demyelination.Οι εμμύελες ίνες των θηλαστικών διαιρούνται σε διακριτές υποπεριοχές, οι οποίες πλαισιώνουν τους κόμβους του Ranvier, στους οποίους βρίσκονται τα τασεοελεγχόμενα κανάλια νατρίου (voltage gated Na channels - Nav). Δίπλα από τον κόμβο του Ranvier βρίσκονται σε διαδοχή οι λεγόμενες παρακομβικές περιοχές (paranodes - PNs), στις οποίες λαμβάνουν χώρα φυσικές αλληλεπιδράσεις των γλοιακών και αξονικών μεμβρανών, οι εγγύς των παρακομβικών περιοχές (juxtaparanodes - JPXs), στις οποίες γίνεται η συσσώρευση των τασεοελεγχόμενων διαύλων καλίου (voltage-gated K channels - VGKCs) και στη συνέχεια το μεσοκομβικό διάστημα (internode). Η συνοχή των παραπάνω υποπεριοχών είναι υψίστης σημασίας για τη λειτουργία του νευράξονα και την επαγωγή του δυναμικού ενεργείας κατά μήκος του. Ισχυρές αλλαγές επί των περιοχών αυτών έχουν αναφερθεί στη Σκλήρυνση κατά Πλάκας (Multiple Sclerosis - MS), συνοδευόμενες από λειτουργικές συνέπειες για την νευρική λειτουργία. Η πρωτεΐνη TAG-1 (Transient Axonal Glycoprotein-1 ή Contactin2 – Cntn2), η οποία εκφράζεται από τον άξονα και το γλοιακό κύτταρο, εντοπίζεται και αυτή στα JXPs και είναι υπεύθυνη για την μοριακή στρατολόγηση και συγκράτηση των VGKCs και της αξονικής πρωτείνης Caspr2 σε αυτές. Επίσης, η TAG-1 έχει ταυτοποιηθεί ως πιθανό αυτοαντιγόνο σε μια υποκατηγορία ασθενών οι οποίοι πάσχουν από MS και η νευρωνική της μορφή έχει βρεθεί να συμμετέχει σε πολλές διεργασίες όπως η κυτταρική μετανάστευση και διαφοροποίηση, η αξονική δεσμίδωση σε διάφορους τύπους νευρικών κυττάρων στο αναπτυσσόμενο κεντρικό νευρικό σύστημα (Central Nervous System - CNS).Στο πρώτο μέρος της παρούσας μελέτης προσπαθήσαμε να προσεγγίσουμε το ρόλο της TAG-1 στη μυελίνωση, χρησιμοποιώντας δύο μοντέλα απομυελίνωσης σε μύες. Στο πρώτο μοντέλο, αυτό της Αυτοάνοσης Πειραματικής Εγκεφαλομυελίτιδας (Experimental Autoimmune Encephalomyelitis - EAE), έγινε η επαγωγή της απομυελίνωσης μετά από την ενεργοποίηση του ανοσοποιητικού συστήματος έναντι μια δομικής πρωτεΐνης της μυελίνης, καταλήγοντας σε παθολογία της λευκής ουσίας του νωτιαίου μυελού και σχετιζόμενα κλινικά συμπτώματα. Απουσία της TAG-1 παρατηρήθηκε καθυστερημένη ανάπτυξη των νευρολογικών συμπτωμάτων, συνδεδεμένη με μειωμένη στρατολόγηση των ανοσορρυθμιστικών Τ λεμφοκυττάρων (regulatory T cells - Tregs) στο νωτιαίο μυελό. Στο δεύτερο απομυελινωτικό μοντέλο γίνεται χρήση μιας τοξίνης (λυσοφωσφατιδυλοχολίνη – lysophosphatidylocholine - LPC) για να επαχθεί τοπική απομυελίνωση του μεσολοβίου (corpus callosum - cc). Μετά την επαγωγή, η TAG-1 εμπλέκεται στην μοριακή στρατολόγηση των μικρογλοιακών και αστρογλοιακών κυττάρων στη περιοχή της απομυελίνωσης, επάγωντας και τη διαφοροποίηση των πρόδρομων κυττάρων των ολιγοδενδροκυττάρων (Oligodendrocyte Precursor Cells – OPCs). Επιπροσθέτως, απουσία της TAG-1 τα VGKCs συσσωρεύονται στα JXPs μέσω ενός εναλλάκτικού μηχανισμού κατά την επαναμυελίνωση.Στο δεύτερο μέρος της μελέτης, αναφέρουμε αλλαγές επί των πρωτεινών των JXPs TAG-1, Caspr2 και VGKCs στην φαινομενικά υγιή λευκή ουσία (normal appearing white matter - NAWM), στις περιοχές γύρω από τις απομυελινωτικές πλάκες (perilesions) και στις απομυελινωμένες περιοχές (lesions or plaques) σε ιστό post-mortem από ασθενείς πάσχοντες από MS σε σχέση με λευκή ουσία ελέγχου. Δείχνουμε ότι η μοριακή οργάνωση και διατήρηση των JXPs βρίσκεται επηρεασμένη σε όλες τις παραπάνω περιοχές μέσω ανάλυσης της πρωτεινικής έκφρασης και των επιπέδων mRNA, αλλά και μέσω πειραμάτων ανοσοϊστοχημείας. Τα τρία μόρια βρέθηκαν να επηρεάζονται σε διαφορετικό βαθμό. Η συσσώρευση της TAG-1 στα JXPs ήταν μειωμένη στη NAWM, ενώ παρατηρήθηκε η διάχυση των TAG-1 και Caspr2 στις περιοχές γύρω και επί των απομυελινωτικών πλακών. Τα VGKCs δεν βρίσκονταν στα JXP σε καμία από τις περιοχές υπό μελέτη. Στο πρωτεϊνικό επίπεδο, αποκαλύψαμε μόνο μια τάση μείωσης των τριών μορίων στις πλάκες, ενώ τα επίπεδα του αξονικού μορίου των PNs, Caspr, βρέθηκαν αυξημένα, πιθανώς λόγω ενός μηχανισμού ομοιόστασης του νευράξονα.Εν κατακλείδι, από τα αποτελέσματα της μελέτης μας προκύπτει η συμμετοχή της TAG-1 σε καινοτόμες βιολογικές διεργασίες κατά την απομυελίνωση και επαναμυελίνωση σε μύες, όπως στην προώθηση της αυτοανοσίας, της μοριακής στρατολόγησης της μικρογλοίας και αστρογλοίας, καθώς και της διαφοροποιήσης των OPCs σε ώριμα ολιγοδενδροκύτταρα (oligodendrocytes - OLs), ικανά να παράξουν ώριμη μυελίνη. Στην χρόνια MS, αποκαλύψαμε για πρώτη φορά την διαφορική διάχυση και ρύθμιση των τριών πρωτεϊνών που καθιστούν το μοριακό σύμπλοκο των JXPs και την ευαισθησία τους στη NAWM, η οποία χαρακτηρίζεται από διάχυτη παθολογία αλλά όχι από απομυελίνωση

Adult adrenal gland scRNA-seq

Adult adrenal gland scRNA-seq dataset. Gene expression matrices (in dgCMatrix format) are provided as RDS files. Cell annotations (cell types, cortex zonations, and genotypes) are provided in CSV format

Polymorphic parasitic larvae cooperate to build swimming colonies luring hosts

Parasites have evolved a variety of astonishing strategies to survive within their hosts, yet the most chal-lenging event in their personal chronicles is the passage from one host to another. It becomes even more complex when a parasite needs to pass through the external environment. Therefore, the free-living stages of parasites present a wide range of adaptations for transmission. Parasitic flatworms from the group Di-genea (flukes) have free-living larvae, cercariae, which are remarkably diverse in structure and behavior. One of the cercariae transmission strategies is to attain a prey-like appearance for the host. This can be done through the formation of a swimming aggregate of several cercariae adjoined together by their tails. Through the use of live observations and light, electron, and confocal microscopy, we described such a supposedly prey-mimetic colony comprising cercariae of two distinct morphotypes. They are functionally specialized: larger morphotype (sailors) enable motility, and smaller morphotype (passengers) presumably facilitate infection. The analysis of local read alignments between the two samples reveals that both cercaria types have identical 18S, 28S, and 5.8S rRNA genes. Further phylogenetic analysis of these ribo-somal sequences indicates that our specimen belongs to the digenean family Acanthocolpidae, likely genus Pleorchis. This discovery provides a unique example and a novel insight into how morphologically and functionally heterogeneous individuals of the same species cooperate to build colonial organisms for the purpose of infection. This strategy bears resemblance to the cooperating castes of the same species found among insects