Molecular mechanisms of pigmented & vascular neurocristopathies

Birth defects affecting derivatives of the stem cell population known as the neural crest are known collectively as congenital neurocristopathies. More frequent forms preferentially affect the palate, eyes and/or heart, but dozens of rarer diseases can affect disseminated systems such as the skin or the peripheral nervous system. While the genetic bases of many specific rare neurocristopathies over the last decade have been elucidated, most remain without molecular diagnosis and are relatively poorly defined as clinical entities.

Our group has historically focused on a subset of cutaneous malformation syndromes, predisposing to lethal complications, due to recurrent post-zygotic mutations found in many adult cancers. These new somatic mutations lead to constitutive activation of enzymes in the affected cell type that transduce growth factor signaling. The resulting organism is a mosaic of affected (mutated) and unaffected (non-mutated) cells, and their interactions during development can lead to pathogenesis.

Preliminary data from our mouse models shows that we can phenocopy other congenital syndromes afflicting fetuses and children by directing the same types of mutations to distinct multipotent neural crest derivatives. This can affect not only their progeny in the skin but also in the heart, the peripheral nervous system or the skull. Characterizing these models and searching for equivalent mutations in relevant patient cohorts can lead to improved diagnosis and new therapeutic approaches for congenital neurocristopathies by repurposing drugs originally developed for targeted chemotherapy.

Genetic causes and modifiers of giant congenital melanocytic nevus

The large and giant congenital melanocytic nevus (CMN) is a visibly conspicuous malformation of the skin, present at birth. It can present as a restricted, stable and benign tumor, or be associated in syndromic form with additional cutaneous, neurological or oncological symptoms.

We study the effects of the molecular signaling pathways shown to be present in CMN in the embryological precursors to pigment cells using multiple systems, each of which corresponds to specific projects underway :

• Surgical and pathology specimens from large congenital melanocytic nevi (CMN)
• Induced pluripotent stem cells from human CMN
• Comparative transcriptomics in primary cultures of mouse cells from neural crest-specific induction of constitutively active BRAF or NRAS mutations
• Phenotypic characterization of mouse models with different onset or compartments of BRAF or NRAS mutations during prenatal and postnatal development, in order to understand cell non-autonomous effects in CMN syndrome

Intracellular effectors of vascular and craniofacial malformations

The long-term goal of this project is to better understand the molecular and embryological origins of congenital vascular malformations, in order to identify therapeutic targets to prevent their postnatal evolution. Recently published data on sporadic or vascular malformations has shown that somatic mutations in genes encoding one or more effectors of the RAS-RAF and PI3K signaling pathways, and propagated in the cellular components of blood vessels, cause these rare, defiguring and sometimes lethal conditions. We also have some evidence that such somatic mutations exist in epistasis to a permissive, heritable genetic background.

Our recent preliminary data from mouse models for the expression of such mutations in the neural crest lineage implicates these signaling pathways not only in vascular but also craniofacial malformations affecting the skull and palate, or in progressive peripheral neuropathies.