TY - JOUR
T1 - Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period
AU - Korotkov, Anatoly
AU - Luinenburg, Mark J
AU - Romagnolo, Alessia
AU - Zimmer, Till S
AU - van Scheppingen, Jackelien
AU - Bongaarts, Anika
AU - Broekaart, Diede W M
AU - Anink, Jasper J
AU - Mijnsbergen, Caroline
AU - Jansen, Floor E
AU - van Hecke, Wim
AU - Spliet, Wim G
AU - van Rijen, Peter C
AU - Feucht, Martha
AU - Hainfellner, Johannes A
AU - Krsek, Pavel
AU - Zamecnik, Josef
AU - Crino, Peter B
AU - Kotulska, Katarzyna
AU - Lagae, Lieven
AU - Jansen, Anna C
AU - Kwiatkowski, David J
AU - Jozwiak, Sergiusz
AU - Curatolo, Paolo
AU - Mühlebner, Angelika
AU - van Vliet, Erwin A
AU - Mills, James D
AU - Aronica, Eleonora
N1 - Funding Information:
The research leading to these results has received funding from the European Union’s Seventh Framework Program (FP7/2007–2013) under grant agreement 602,102 (EPITARGET; EAvV, EA) and 602,391 (EPISTOP; EA, MF, PK, KK, LL, ACJ, DJK, SJ, PC, AM, JDM, AM, JvS, FEJ), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 642881 (ECMED; AK, EA, EAvV) and no. 722053 (EU-GliaPhD; TSZ, EA, EAvV), as well as no. 952455 (EpiEpiNet, EA, EAvV, JM) and the Dutch Epilepsy Foundation, project number 16–05 (EAvV, DWMB) and 20–02 (AM, MJL).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/1/15
Y1 - 2022/1/15
N2 - Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70–80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes – cell-adhesion molecule contactin-3. Methods: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1–48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0–44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0–3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. Results: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = − 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0–3 years old (fold change = − 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). Conclusions: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.
AB - Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70–80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes – cell-adhesion molecule contactin-3. Methods: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1–48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0–44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0–3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. Results: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = − 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0–3 years old (fold change = − 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). Conclusions: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.
KW - Cell adhesion
KW - Cerebral cortex development
KW - Epilepsy
KW - mTORopathies
KW - Neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85122985439&partnerID=8YFLogxK
U2 - 10.1186/s11689-022-09416-2
DO - 10.1186/s11689-022-09416-2
M3 - Article
C2 - 35030990
SN - 1866-1947
VL - 14
SP - 1
EP - 16
JO - Journal of neurodevelopmental disorders
JF - Journal of neurodevelopmental disorders
IS - 1
M1 - 8
ER -