NR2F1 regulates a Schwann cell precursor-vs-melanocyte cell fate switch in a mouse model of Waardenburg syndrome type IV.

Waardenburg syndrome type 4 (WS4) combines abnormal development of neural crest cell (NCC)-derived melanocytes (causing depigmentation and inner ear dysfunction) and enteric nervous system (causing aganglionic megacolon). The full spectrum of WS4 phenotype is present in Spot mice, in which an insertional mutation close to a silencer element leads to NCC-specific upregulation of the transcription factor-coding gene Nr2f1. These mice were previously found to develop aganglionic megacolon because of NR2F1-induced premature differentiation of enteric neural progenitors into enteric glia. Intriguingly, this prior work also showed that inner ear dysfunction in Spot mutants specifically affects balance but not hearing, consistent with the absence of melanocytes in the vestibule only. Here, we report an analysis of the effect of Nr2f1 upregulation on the development of both inner ear and skin melanocytes, also taking in consideration their origin relative to the dorsolateral and ventral NCC migration pathways. In the trunk, we found that NR2F1 overabundance in Spot NCCs forces dorso-laterally migrating melanoblasts to abnormally adopt a Schwann cell precursor (SCP) fate and conversely prevents ventrally migrating SCPs to normally adopt a melanoblast fate. In the head, Nr2f1 upregulation appears not to be uniform, which might explain why SCP-derived melanocytes do colonize the cochlea while non-SCP-derived melanocytes cannot reach the vestibule. Collectively, these data point to a key role for NR2F1 in the control of SCP-vs-melanocyte fate choice and unveil a new pathogenic mechanism for WS4. Moreover, our data argue against the proposed existence of a transit-amplifying compartment of melanocyte precursors in hair follicles.

Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease.

Hirschsprung disease is a congenital malformation where ganglia of the neural crest-derived enteric nervous system are missing over varying lengths of the distal gastrointestinal tract. This complex genetic condition involves both rare and common variants in dozens of genes, many of which have been functionally validated in animal models. Modifier loci present in the genetic background are also believed to influence disease penetrance and severity, but this has not been frequently tested in animal models. Here, we addressed this question using Holstein mice in which aganglionosis is due to excessive deposition of collagen VI around the developing enteric nervous system, thereby allowing us to model trisomy 21-associated Hirschsprung disease. We also asked whether the genetic background might influence the response of Holstein mice to GDNF enemas, which we recently showed to have regenerative properties for the missing enteric nervous system. Compared to Holstein mice in their original FVB/N genetic background, Holstein mice maintained in a C57BL/6N background were found to have a less severe enteric nervous system defect and to be more responsive to GDNF enemas. This change of genetic background had a positive impact on the enteric nervous system only, leaving the neural crest-related pigmentation phenotype of Holstein mice unaffected. Taken together with other similar studies, these results are thus consistent with the notion that the enteric nervous system is more sensitive to genetic background changes than other neural crest derivatives.

Dhh-expressing Schwann cell precursors contribute to skin and cochlear melanocytes, but not to vestibular melanocytes.

For a long time, melanocytes were believed to be exclusively derived from neural crest cells migrating from the neural tube toward the developing skin. This notion was then challenged by studies suggesting that melanocytes could also be made from neural crest-derived Schwann cell precursors (SCPs) on peripheral nerves. A SCP origin was inferred from lineage tracing studies in mice using a Plp1 promoter-controlled Cre driver transgene (Plp1-CreERT2) and a fluorescent Rosa26 locus-controlled Cre reporter allele (Rosa26FloxSTOP-YFP ). However, doubts were raised in part because another SCP-directed Cre driver controlled by the Dhh promoter (Dhh-Cre) was apparently unable to label melanocytes when used with a non-fluorescent Rosa26 locus-controlled Cre reporter (Rosa26FloxSTOP-LacZ ). Here, we report that the same Dhh-Cre driver line can efficiently label melanocytes when used in a pure FVB/N background together with the fluorescent instead of the non-fluorescent Rosa26 locus-controlled Cre reporter. Our data further suggest that the vast majority of skin melanocytes are SCP-derived. Interestingly, we also discovered that SCPs contribute inner ear melanocytes in a region-specific manner, extensively contributing to the cochlea but not to the vestibule.

AMPK and autophagy control embryonic elongation as part of a RhoA-like morphogenic program in nematode.

Autophagy is the process where cytosolic components are digested by the cell. This process is required for cell survival in stressful conditions. It was also shown to control cell division and more recently, cell morphology and migration. We characterized signalling pathways enabling embryonic epidermal cells of the nematode Caenorhabditis elegans to elongate along their antero-posterior axis. Previous studies revealed that epidermal cells can adopt either a RhoA-like or a Rac1-like morphogenic program. We show here that the AMP-activated protein kinase (AMPK) and genes controlling autophagy are required for proper elongation of epidermal cells following the RhoA-like program and are dispensable for other cells. This suggests that AMPK-autophagy is used by the embryo to fuel the most energy-demanding morphogenic processes promoting early elongation.