Friday, May 3, 2024
5/3/2024
ABSTRACT Cognitive impairments, which characterize many neurodevelopmental disorders, such as autism spectrum disorder, schizophrenia, and intellectual disability, likely arise from aberrant neurodevelopmental processes. Copy number variations (CNVs), such as the 22q11.2 hemizygous deletion, confer a very high risk for specific cognitive deficits. We demonstrated that in mice, constitutive heterozygosity of Tbx1, a transcription factor gene within the 22q11.2 CNV, resulted in reduced mature oligodendrocytes and myelination, and decreased levels of Ng2 mRNA, a gene required for the production of oligodendrocyte precursor cells. These mice showed reduced speed in completing a task in attentional set-shifting and increased latency in spatial memory acquisition. Strikingly, conditional initiation of Tbx1 heterozygosity in stem cells during the neonatal (P1–P5), but not the peripubertal (P21–P25) period, reduced the speed to perform a cognitive task in mice in a way similar to constitutive Tbx1 heterozygous mice. Our results suggest that TBX1 expression during the neonatal developmental period is critical for the normal development of myelin and cognitive speed; however, the mechanism of TBX1 action is unknown. It is not known whether TBX1 expression during the neonatal period is essential for the proliferation of stem cells that give rise to oligodendrocyte precursor cells for myelination, which affects cognitive speed. Here, I propose experiments to increase our understanding of post-embryonic mechanisms underlying the cognitive deficits associated with TBX1 deficiency. We hypothesize that TBX1 is essential for the development of cognitive speed through the regulation of neonatal stem cells that produce oligodendrocytes and myelination. To test this hypothesis, we will use conditional Tbx1 heterozygous mouse models to induce Tbx1 heterozygosity in stem cells during the neonatal or postnatal periods or in oligodendrocyte precursor cells during the neonatal period. In these mice, we will measure cognitive speed in spontaneous alternation and attentional set-shifting (Aim 1) and assess cellular phenotypes in neonatal stem cells, oligodendrocytes and their precursor cells, and myelination (Aim 2). Moreover, we have identified thousands of potential target genes of the TBX1 transcription factor by ChIP-seq, among which FoxG1 is the only gene that is associated with stem cells, neurodevelopmental disorders, and cerebral dysmyelination. Therefore, we will determine the role of TBX1 in FoxG1 regulation (Aim 3). There are no reliable diagnostic markers or cures for neurodevelopmental disorders. The results from this research will significantly advance our knowledge of the neurobiological mechanisms that lead to neurodevelopmental disorders, a prerequisite for the development of treatments based on precision medicine. Moreover, the multidisciplinary and translational aspects of the proposed training plan will provide rigorous training for the applicant to transition to an independent physician-scientist.
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