Neural crest Notch/Rbpj signaling regulates olfactory gliogenesis and neuronal migration.

The neural crest-derived ensheathing glial cells of the olfactory nerve (OECs) are unique in spanning both the peripheral and central nervous systems: they ensheathe bundles of axons projecting from olfactory receptor neurons in the nasal epithelium to their targets in the olfactory bulb. OECs are clinically relevant as a promising autologous cell transplantation therapy for promoting central nervous system repair. They are also important for fertility, being required for the migration of embryonic gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode along terminal nerve axons to the medial forebrain, which they enter caudal to the olfactory bulbs. Like Schwann cell precursors, OEC precursors associated with the developing olfactory nerve express the glial marker myelin protein zero and the key peripheral glial transcription factor Sox10. The transition from Schwann cell precursors to immature Schwann cells is accelerated by canonical Notch signaling via the Rbpj transcription factor. Here, we aimed to test the role of Notch/Rbpj signaling in developing OECs by blocking the pathway in both chicken and mouse. Our results suggest that Notch/Rbpj signaling prevents the cranial neural crest cells that colonize the olfactory nerve from differentiating as neurons, and at later stages contributes to the guidance of GnRH neurons.

Evidence for a Notch1-mediated transition during olfactory ensheathing cell development.

Olfactory ensheathing cells (OECs) are a unique glial population found in both the peripheral and central nervous system: they ensheath bundles of unmyelinated olfactory axons from their peripheral origin in the olfactory epithelium to their central synaptic targets in the glomerular layer of the olfactory bulb. Like all other peripheral glia (Schwann cells, satellite glia, enteric glia), OECs are derived from the embryonic neural crest. However, in contrast to Schwann cells, whose development has been extensively characterised, relatively little is known about their normal development in vivo. In the Schwann cell lineage, the transition from multipotent Schwann cell precursor to immature Schwann cell is promoted by canonical Notch signalling. Here, in situ hybridisation and immunohistochemistry data from chicken, mouse and human embryos are presented that suggest a canonical Notch-mediated transition also occurs during OEC development.

Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo.

Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain) is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs), we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1) into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

Making It New Again: Insight Into Liver Development, Regeneration, and Disease From Zebrafish Research.

The adult liver of most vertebrates is predominantly comprised of hepatocytes. However, these cells must work in concert with biliary, stellate, vascular, and immune cells to accomplish the vast array of hepatic functions required for physiological homeostasis. Our understanding of liver development was accelerated as zebrafish emerged as an ideal vertebrate system to study embryogenesis. Through work in zebrafish and other models, it is now clear that the cells in the liver develop in a coordinated fashion during embryogenesis through a complex yet incompletely understood set of molecular guidelines. Zebrafish research has uncovered many key players that govern the acquisition of hepatic potential, cell fate, and plasticity. Although rare, some hepatobiliary diseases-especially biliary atresia-are caused by developmental defects; we discuss how research using zebrafish to study liver development has informed our understanding of and approaches to liver disease. The liver can be injured in response to an array of stressors including viral, mechanical/surgical, toxin-induced, immune-mediated, or inborn defects in metabolism. The liver has thus evolved the capacity to efficiently repair and regenerate. We discuss the emerging field of using zebrafish to study liver regeneration and highlight recent advances where zebrafish genetics and imaging approaches have provided novel insights into how cell plasticity contributes to liver regeneration.