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

Abstract

SUMMARYThe 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 nerveassociated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…However, our data on melanocyte migration toward their target location in the cochlea, which to our knowledge has not been shown before in such clarity, suggests that cochlear melanocytes in humans migrate through the periotic mesenchyme from the opposite side. In agreement, several studies in mice embryos show the presence of neural crest derivatives or melanocytes near this part of the otic vesicle around embryonic day 10.5 (Steel et al, 1992; Freyer et al, 2011; Adameyko et al, 2012; Wakaoka et al, 2013; Sandell et al, 2014). Therefore, although the peripheral glial cells in the cochlea originate from the migratory wave of neural crest cells from rhombomere 4, we now hypothesize that cochlear melanocytes originate from a different wave of neural crest cells, namely those delaminating from the region at rhombomere 6, at the location of the developing glossopharyngeal nerve (cranial nerve IX) and the third pharyngeal arch.…”

“…As cochlear development in humans progresses slower than in mice (as a rule of thumb, one day of rodent cochlear development corresponds to one week in humans), this permits a more explicit visualization of developmental events. Recently, it has been reported that cranial melanocytes can arise from Schwann cell precursors migrating together with outgrowing nerves (Adameyko et al, 2009; Adameyko et al, 2012). As Schwann cell precursors arrive in the cochlea via the cochlear nerve (Sandell et al, 2014), it is tempting to propose that melanocytes (precursors) may travel along the same path.…”

miR-488 acts as a tumor suppressor gene in gastric cancer

“…However, in other studies, miR-638 was found to protect melanoma cells from apoptosis and autophagy [25], and promote starvation-or rapamycin-induced autophagy in ESCC and breast cells (KYSE450 and MCF-7) [26]. SOX2, a member of SRY-related HMG-box transcription factors families, is a well-established regulator of cell differentiation and development [27,28]. More than that, accumulating studies suggest that SOX2 acts as an oncogene in some cancers, such as skin squamous-cell carcinoma [29,30], lung squamouscell carcinoma [31,32], ovarian carcinoma [33], osteosarcomas [34] and glioblastoma [35].…”

Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3

“…These melanocytes differentiate at late stages relative to pigment cells directly generated from the NC. Thus, in addition to late emigrating/early differentiating NC-derived melanocytes, a subset of early delaminating NC cells that migrate dorsoventrally and later become SCPs in association with the growing nerves can develop either into mature SCs if they remain in contact with nerve fibers or generate melanocytes if they detach from the nerve environment (3,9,10). Except for their common origin from the NC, the relationship between these two melanocyte subsets, at both cellular and molecular levels, remains to be elucidated.…”