Thesis presented September 20, 2016

Abstract:
Incontinentia pigmenti (IP, OMIM # 308300) is an X-linked genetic disease which is lethal in boys. In girls, it causes a skin disease that begins soon after birth and evolves along a complex sequence of events involving inflammation, cell hyperproliferation and apoptosis. IP patients can also suffer from ocular, dental and brain anomalies. Brain defects affect about 30% of patients and are characterized by epilepsy and/or cognitive/motor disorders. The IP-causing gene encodes the protein NEMO, an essential component of the signaling pathway NF-kB that regulates immunity, inflammation, proliferation and cell death process. In approximately 70% of IP patients, the same chromosomal rearrangement eliminates almost completely the NEMO gene, generating a loss of activation of the NF-kB pathway. Invalidation of the gene in Nemo mice (Nemo ^+/- females) provides a model for the study of the cutaneous events observed in IP patients.
In order to better define the IP brain anomalies of patients and their origin, which remains obscure, we analyzed the brains of Nemo ^+/- mice. We show here, using a MRI protocol adapted for brain of seven days (P7), that anomalies are detected in a fraction of the samples. These anomalies are heterogeneous and localized in a non-specific manner, as in humans. They include diffuse hemorrhagic areas, cavities and atrophy of the corpus callosum. This demonstrates the usefulness of the murine system Nemo ^+/- to also study the IP patient's brain defects. Interestingly, these brain lesions can be detected before birth, at day 18 of development, and are not caused by a neuron, astrocyte or oligodendrocyte dysfunction. Using an immune approach coupled to an in toto analysis of P7 brain, after treating them by chemicals to induce their transparency (iDISCO technique), we detected vascular anomalies, suggesting that this compartment causes the brain defects in IP patients.


Keywords:
Incontinentia pigmenti, NEMO, NF-kB, Neurobiology

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