Lebenslauf

Publikationen

2019

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/− mice.
Pringsheim M,, Mitter D, Schröder S, Warthemann R, Plümacher K, Kluger G, Baethmann M, Bast T, Braun S, Büttel HM, Conover E, Courage C, Datta AN, Eger A, Grebe TA, Hasse‐Wittmer A, Heruth M, Höft K, Kaindl AM, Karch S, Kautzky T, Korenke GC, Kruse B, Lutz RE, Omran H, Patzer S, Philippi H, Ramsey K, Rating T, Rieß A, Schimmel M, Westman R, Zech FM, Zirn B, Ulmke PA, Sokpor G, Tuoc T, Leha A, Staudt M, Brockmann K.
Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.735, 2019.
abstract link

Objective
FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations.

Methods
We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re‐analysis of all 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/− mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies.

Results
Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Thickening of the fornices was not reported previously in FOXG1 syndrome. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix.

Interpretation
Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

2018

Chromatin remodeling BAF155 subunit regulates the genesis of basal progenitors in developing cortex .
Narayanan R, Pham L, Kerimoglu C, Watanabe T, Hernandez RC, Sokpor G, Ulmke PA, Kiszka KA, Tonchev AB, Rosenbusch J, Seong RH, Teichmann U, Frahm J, Fischer F, Bonn S, Stoykova A, Staiger JF, Tuoc T.
iScience (Cell Press), DOI: https://doi.org/10.1016/j.isci.2018.05.014, 2018.
abstract link

The abundance of basal progenitors (BPs) - basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling expression of genes that are involved in bIP specification, cell-cell interaction and establishment of adherens junction. In PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through regulation of human RG-specific genes (such as Foxn4) that possibly acquired evolutionary significance.