Tags

Type your tag names separated by a space and hit enter

Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis.
Front Psychiatry 2019; 10:416FP

Abstract

Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported, and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analyzed the regulation and expression of the pseudoautosomal region 2 gene SPRY3, which is adjacent to X chromosome-linked TMLHE, a known autism susceptibility gene. SPRY3 is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse Spry3 is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of p75NTR, which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate SPRY3 expression in these lobules could interact with TrkB and p75NTR signaling pathways resulting in Purkinje cell pathology. We report preliminary characterization of X and Y chromosome-linked regulatory sequences upstream of SPRY3, which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to trans-acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked SPRY3. This proposed male-specific mechanism could contribute to the male bias in autism prevalence.

Authors+Show Affiliations

School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31275178

Citation

Ning, Zhenfei, et al. "Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis." Frontiers in Psychiatry, vol. 10, 2019, p. 416.
Ning Z, Williams JM, Kumari R, et al. Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis. Front Psychiatry. 2019;10:416.
Ning, Z., Williams, J. M., Kumari, R., Baranov, P. V., & Moore, T. (2019). Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis. Frontiers in Psychiatry, 10, p. 416. doi:10.3389/fpsyt.2019.00416.
Ning Z, et al. Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis. Front Psychiatry. 2019;10:416. PubMed PMID: 31275178.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposite Expression Patterns of Spry3 and p75NTR in Cerebellar Vermis Suggest a Male-Specific Mechanism of Autism Pathogenesis. AU - Ning,Zhenfei, AU - Williams,John M, AU - Kumari,Romika, AU - Baranov,Pavel V, AU - Moore,Tom, Y1 - 2019/06/18/ PY - 2018/12/20/received PY - 2019/05/24/accepted PY - 2019/7/6/entrez PY - 2019/7/6/pubmed PY - 2019/7/6/medline KW - SPRY3 KW - TMLHE KW - autism KW - carnitine KW - cerebellum KW - p75NTR KW - pseudoautosomal region SP - 416 EP - 416 JF - Frontiers in psychiatry JO - Front Psychiatry VL - 10 N2 - Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported, and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analyzed the regulation and expression of the pseudoautosomal region 2 gene SPRY3, which is adjacent to X chromosome-linked TMLHE, a known autism susceptibility gene. SPRY3 is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse Spry3 is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of p75NTR, which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate SPRY3 expression in these lobules could interact with TrkB and p75NTR signaling pathways resulting in Purkinje cell pathology. We report preliminary characterization of X and Y chromosome-linked regulatory sequences upstream of SPRY3, which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from SPRY3 acts as a silencer of Y-linked SPRY3 expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to trans-acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked SPRY3. This proposed male-specific mechanism could contribute to the male bias in autism prevalence. SN - 1664-0640 UR - https://www.unboundmedicine.com/medline/citation/31275178/Opposite_Expression_Patterns_of_Spry3_and_p75NTR_in_Cerebellar_Vermis_Suggest_a_Male-Specific_Mechanism_of_Autism_Pathogenesis L2 - https://dx.doi.org/10.3389/fpsyt.2019.00416 DB - PRIME DP - Unbound Medicine ER -