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Open Access 01-12-2016 | Research

Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis complex (TSC): evidence from layer-specific marker expression

Authors: Angelika Mühlebner, Anand M. Iyer, Jackelien van Scheppingen, Jasper J. Anink, Floor E. Jansen, Tim J. Veersema, Kees P. Braun, Wim G. M. Spliet, Wim van Hecke, Figen Söylemezoğlu, Martha Feucht, Pavel Krsek, Josef Zamecnik, Christian G. Bien, Tilman Polster, Roland Coras, Ingmar Blümcke, Eleonora Aronica

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2016

Abstract

Background

Tuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway. Cortical tubers represent typical lesions of the central nervous system (CNS) in TSC. The pattern of cortical layering disruption observed in brain tissue of TSC patients is not yet fully understood, and little is known about the origin and phenotype of individual abnormal cell types recognized in tubers.

Methods

In the present study, we aimed to characterize dysmorphic neurons (DNs) and giant cells (GCs) of cortical tubers using neocortical layer-specific markers (NeuN, SMI32, Tbr1, Satb2, Cux2, ER81, and RORβ) and to compare the features with the histo-morphologically similar focal cortical dysplasia (FCD) type IIb. We studied a cohort of nine surgically resected cortical tubers, five FCD type IIb, and four control samples using immunohistochemistry and in situ hybridization.

Results

Cortical tuber displayed a prominent cell loss in all cortical layers. Moreover, we observed altered proportions of layer-specific markers within the dysplastic region. DNs, in both tubers and FCD type IIb, were found positive for different cortical layer markers, regardless of their laminar location, and their immunophenotype resembles that of cortical projection neurons.

Conclusions

These findings demonstrate that, similar to FCD type IIb, cortical layering is markedly disturbed in cortical tubers of TSC patients. Distribution of these disturbances is comparable in all tubers and suggests a dysmaturation affecting early and late migratory patterns, with a more severe impairment of the late stage of maturation.

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Title: Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis complex (TSC): evidence from layer-specific marker expression
Authors: Angelika Mühlebner
Anand M. Iyer
Jackelien van Scheppingen
Jasper J. Anink
Floor E. Jansen
Tim J. Veersema
Kees P. Braun
Wim G. M. Spliet
Wim van Hecke
Figen Söylemezoğlu
Martha Feucht
Pavel Krsek
Josef Zamecnik
Christian G. Bien
Tilman Polster
Roland Coras
Ingmar Blümcke
Eleonora Aronica
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neurodevelopmental Disorders / Issue 1/2016
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI: https://doi.org/10.1186/s11689-016-9142-0

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Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis complex (TSC): evidence from layer-specific marker expression

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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