Haploinsufficiency of the class I bHLH transcription factor TCF4 causes Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder, while common variants in the TCF4 gene have been identified as susceptibility factors for schizophrenia. It remains largely unknown, which brain regions are dependent on TCF4 for their development and function. We systematically analyzed the expression pattern of TCF4 in the developing and adult mouse brain. We used immunofluorescent staining to identify candidate regions whose development and function depend on TCF4. In addition, we determined TCF4 expression in the developing rhesus monkey brain and in the developing and adult human brain through analysis of transcriptomic datasets and compared the expression pattern between species. Finally, we morphometrically and histologically analyzed selected brain structures in Tcf4-haploinsufficient mice and compared our morphometric findings to neuroanatomical findings in PTHS patients. TCF4 is broadly expressed in cortical and subcortical structures in the developing and adult mouse brain. The TCF4 expression pattern was highly similar between humans, rhesus monkeys, and mice. Moreover, Tcf4 haploinsufficiency in mice replicated structural brain anomalies observed in PTHS patients. Our data suggests that TCF4 is involved in the development and function of multiple brain regions and indicates that its regulation is evolutionary conserved. Moreover, our data validate Tcf4-haploinsufficient mice as a model to study the neurodevelopmental basis of PTHS.

Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.

The intellectual disability gene, Sox11, encodes for a critical neurodevelopmental transcription factor with functions in precursor survival, neuronal fate determination, migration and morphogenesis. The mechanisms regulating SOX11’s activity remain largely unknown. Mass spectrometric analysis uncovered that SOX11 can be post-translationally modified by phosphorylation. Here, we report that phosphorylatable serines surrounding the high-mobility group box modulate SOX11’s transcriptional activity. Through Mass Spectrometry (MS), co-immunoprecipitation assays and in vitro phosphorylation assays followed by MS we verified that protein kinase A (PKA) interacts with SOX11 and phosphorylates it on S133. In vivo replacement of SoxC factors in developing adult-generated hippocampal neurons with SOX11 S133 phospho-mutants indicated that phosphorylation on S133 modulates dendrite development of adult-born dentate granule neurons, while reporter assays suggested that S133 phosphorylation fine-tunes the activation of select target genes. These data provide novel insight into the control of the critical neurodevelopmental regulator SOX11 and imply SOX11 as a mediator of PKA-regulated neuronal development.

Perturbation of neuronal activity-regulated transcriptional networks has been increasingly linked to the pathophysiology of various neurodevelopmental and psychiatric diseases ([Ebert et al., 2013][1]). Transcription factors mediate a significant part of the activity-dependent response of neurons by

Einleitung Für Secukinumab, einen rein humanen monoklonalen anti-IL-17A Antikörper, wurde in verschiedenen kontrollierten klinischen Studien eine deutliche Wirksamkeit und ein günstiges Sicherheitsprofil bei der Behandlung von moderater bis schwerer Psoriasis (PsO) nachgewiesen. Hier berichten wir über die abschließenden Wirksamkeits- und Sicherheitsdaten der deutschen