Funktion av humana Y kromosom gener i centrala nervsystemet under tidigt human utvecklingen

Tidsperiod: 2016-01-01 till 2018-12-31

Projektledare: Elena Jazin

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 2 100 000 SEK

The functions of Y-chromosome encoded genes are not only of interest for fertility research, but they are also relevant for studies of sex differences in brain and behaviour during early human development. An important first step to understand the functional relevance of Y-encoded genes is to investigate whether X and Y homologous are expressed in a sex-specific manner in specific cells or tissues in the central nervous system (CNS). These experiments cannot be performed using conventional in-situ hybridization or immunofluorescence techniques because of cross-hybridization of probes due to high sequence similarity between X and Y homologous genes. We have designed a strategy, using padlock rolling circle technology, to distinguish expression of PCDH11X, PCDH11Y, NLGN4X and NLGN4Y. We plan to use similar strategies to disentangle the dimorphic expression of other X and Y homologous genes, as well as of novel non-annotated sexually dimorphic genes that we have recently discovered by RNA sequencing. We will also perform functional studies by knockdown or over-expression of these genes in human embryonic stem cells. Before expression levels of these cells are modified, we will start our investigations by the study of the normal proliferation rate, cell-cell interactions, neurite and axon formation in stem cells of male and female origin differentiated to neurons, to evaluate possible effects of the presence of a Y chromosome in these cells. These investigations are of importance not only to understand normal sex differences in the development of the brain, but also may shed light on the mechanisms of abnormal development in psychiatric conditions known to have profound sex bias such as autism and certain types of depression.