Altered development and function of the spinal cord in Down syndrome

Boston University Medical Campus, Boston MA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Newborns with Down syndrome (DS) are hypotonic and exhibit disturbances in movement production and postural control. Their acquisition of motor skills in infancy is significantly delayed, negatively impacting their gait, reflexes, and fie motor control throughout life. Work investigating the etiology of DS-related motor deficits has been largely focused on the cerebellum, yet preliminary work in our lab has for the first time elucidated substantial cytoarchitectural as well as gene expression differences between spinal cords (SCs) in trisomic mice and their euploid controls. Furthermore, two genes critically involved in SC development, known as Oligodendrocyte transcription factor 1 and 2 (Olig1/2) are triplicated in both people with DS and trisomic mouse models. Both Olig genes are expressed in a progenitor domain by a bipotential population of cells that can differentiate into either motor neurons (MNs) or oligodendrocytes (OLs). Additionally, Olig2 plays a role in interneuron (IN) specification through cross-repression. The fate-designation and maturation of precursor cells of these three cell types are essential for the proper development and function of the SC. Thus, the triplication of Olig1/2, coupled with their role in SC development, suggests that the Olig genes play a major role in SC abnormalities in DS. In this project, we propose to identify biomarkers of trisomic SC development and function in the adult, perinatal, and embryonic Ts65Dn mouse model of DS. We also plan to elucidate the specific role of Olig1/2 in trisomic SC development by utilizing a `gene dosage reduced' Ts65Dn model disomic for Olig1/2. Using a combination of behavioral testing, gene expression analyses, and immunohistochemical staining we will comprehensively assess how changes in multiple neuronal and glial populations influence SC development and motor behavior in trisomic animals while examining the degree to which triplication of Olig1/2 affects cell population dynamics in the cord. By targeting the Olig genes, this work is slated to reveal the specific molecular underpinnings of SC-related motor deficits in DS with potential for therapeutic exploitation to correct such debilitating and impactful life-long deficits.