Search

Down syndrome (DS) is caused by triplication of human chromosome 21 (HSA21) and is the most common genetic form of intellectual disability. It is unknown precisely how triplication of HSA21 results in the intellectual disability, but it is thought that the global transcriptional dysregulation caused by trisomy 21 perturbs multiple aspects of neurodevelopment that cumulatively contribute to its etiology. While the characteristics associated with DS can arise from any of the genes triplicated on HSA21, in this work we focus on oligodendrocyte transcription factor 2 (OLIG2). The progeny of neural progenitor cells (NPCs) expressing OLIG2 are likely to be involved in many of the cellular changes underlying the intellectual disability in DS. To explore the fate of OLIG2+ neural progenitors, we took advantage of two distinct models of DS, the Ts65Dn mouse model and induced pluripotent stem cells (iPSCs) derived from individuals with DS. Our results from these two systems identified multiple perturbations in development in the cellular progeny of OLIG2+ NPCs. In Ts65Dn, we identified alterations in neurons and glia derived from the OLIG2 expressing progenitor domain in the ventral spinal cord. There were significant differences in the number of motor neurons and interneurons present in the trisomic lumbar spinal cord depending on age of the animal pointing both to a neurodevelopment and a neurodegeneration phenotype in the Ts65Dn mice. Of particular note, we identified changes in oligodendrocyte (OL) maturation in the trisomic mice that are dependent on spatial location and developmental origin. In the dorsal corticospinal tract, there were significantly fewer mature OLs in the trisomic mice, and in the lateral funiculus we observed the opposite phenotype with more mature OLs being present in the trisomic animals. We then transitioned our studies into iPSCs where we were able to pattern OLIG2+ NPCs to either a spinal cord-like or a brain-like identity and study the OL lineage that differentiated from each progenitor pool. Similar to the region-specific dysregulation found in the Ts65Dn spinal cord, we identified perturbations in trisomic OLs that were dependent on whether the NPCs had been patterned to a brain-like or spinal cord-like fate. In the spinal cord-like NPCs, there was no difference in the proportion of cells expressing either OLIG2 or NKX2.2, the two transcription factors whose co-expression is essential for OL differentiation. Conversely, in the brain-like NPCs, there was a significant increase in OLIG2+ cells in the trisomic culture and a decrease in NKX2.2 mRNA expression. We identified a sonic hedgehog (SHH) signaling based mechanism underlying these changes in OLIG2 and NKX2.2 expression in the brain-like NPCs and normalized the proportion of trisomic cells expressing the transcription factors to euploid levels by modulating the activity of the SHH pathway. Finally, we continued the differentiation of the brain-like and spinal cord-like NPCs to committed OL precursor cells (OPCs) and allowed them to mature. We identified an increase in OPC production in the spinal cord-like trisomic culture which was not present in the brain-like OPCs. Conversely, we identified a maturation deficit in the brain-like trisomic OLs that was not present in the spinal cord-like OPCs. These results underscore the importance of regional patterning in characterizing changes in cell differentiation and fate in DS. Together, the findings presented in this work contribute to the understanding of the cellular and molecular etiology of the intellectual disability in DS and in particular the contribution of cells differentiated from OLIG2+ progenitors.

Children with disabilities are at high risk for several forms of maltreatment, including abuse and neglect (Ammerman, Hersen, Van Hasselt, Lubetsky, & Sieck, 1994; Sullivan & Knutson, 1998b), and children with hearing and communication disorders comprise a substantial portion of children at risk (e.g., Sullivan & Knutson, 2000). For example, some literature investigating the parenting practices of parents raising children and adolescents with hearing and communication disorders suggests that these parents have a tendency to use physically harsh discipline practices (Knutson, Johnson, & Sullivan, 2004; Sullivan & Knutson, 1998b). Further, high prevalence rates of emotional and behavioral problems are documented in these youth (e.g., Greenberg & Kusche, 1989; Hindley, 1997; Prizant, Audet, Burke, & Hummel, 1990). Despite these findings, a limited amount of research focuses on understanding factors related to these undesired outcomes. Therefore, this study investigates the relationships among dimensions of parents' psychological functioning and parent-child interactive processes in a culturally diverse, national sample of families raising children and adolescents with hearing and communication disorders. Results suggest that parents' stress, depression, and anxiety as well as parent-child communication and involvement are important correlates of discipline practices and subsequent child behavior in families raising children and adolescents with hearing and communication disorders. Additionally, psychological aggression and parents' depression are highly predictive factors in the use of corporal punishment. Also, psychological aggression and parenting stress are highly predictive of reported youth behavior problems. The information gained from this investigation may provide direction for assessment and therapeutic intervention with parents of children and adolescents who have hearing and communication disorders.

A majority of research regarding disruptive behavior disorders in youth has focused primarily upon Caucasian children and adolescents. As a result, more investigation of the unique characteristics of youth from ethnically diverse backgrounds, particularly those from Hispanic American and African American backgrounds, is needed (Balls Organista, Organista, & Kurasaki, 2003). This study investigated the relationships between several characteristics (e.g., ethnic identity, socioeconomic status, social acceptance, and emotional and behavioral symptoms) of early adolescents belonging to diverse ethnic groups. Results suggested that socioeconomic status and degree of early adolescents' social acceptance were important factors in predicting the development of internalizing and externalizing behavior problems in this age group. Additionally, perceived social acceptance moderated significantly the relationships between SES and depression, anxiety, and self-concept. Considering these results, useful treatments may be developed that enhance early adolescents' abilities to assess realistically their own social skills and interact appropriately within different social spheres. Increased self-appraisals of acceptance within social situations may modify negative effects (e.g., higher reports of anxiety and depression) of extreme socioeconomic circumstances, particularly for early adolescents experiencing low-income or poverty conditions within their family and/or their community.