The corpus callosum (CC) provides interhemispheric communication essential for cognitive and associative processes, with critical roles in several higher order functions including sensory processing, motor coordination, and language acquisition and formation. Malformation of the CC has devastating functional consequences; agenesis and hypoplasia of the CC is linked to several conditions associated with severe neurological and cognitive disabilities. In addition, anatomical and physiological deficits of the CC also have been commonly reported in several neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). Yet, the cellular and molecular mechanisms involved with the malformation of the CC in these disorders remain undefined. Our current understanding of CC development is exclusively limited to factors and mechanisms involved with the early axon guidance phase, as well as those involved with the later myelination and synaptogenesis stages. However, the regulation of early postnatal CC refinement, in which initially produced callosal axons are selectively preserved or eliminated, remains completely unknown and is vastly understudied. Our major goal is to elucidate the mechanisms underlying the critical but vastly unexplored early postnatal processes governing CC development. This understanding will be crucial in shedding light on the pathogenesis of callosal abnormalities in neurodevelopmental disorders. Along with axon elimination, axon preservation is critical in maintaining the appropriate neuronal connections during this developmental refinement period, which leaves a lasting impact throughout the life of the organism. Our preliminary investigation has led to us to an intriguing hypothesis that the autism-linked gene, Plexin-A4, selectively preserves a subset of callosal axons during early postnatal CC refinement via the inhibition of caspase-mediated tubulin cleavage. In this proposed project, we will first establish the as-of-yet unconfirmed developmental elimination of callosal axons in the mouse CC (Aim 1). We will then test our hypothesis using various genetic and molecular biological techniques through our mouse model of CC refinement (Aim 2). We will then define molecular links between Plexin-A4 and caspase inhibition, a relationship which has previously been unknown, as well as identify novel autism-linked genes that are essential in the postnatal maintenance/elimination of callosal axons, using a unique combination of mass spectrometry and single-cell RNA sequencing (Aim 3). These results will, for the first time, validate the use of a mouse model to study the fundamental process of axon preservation during the postnatal refinement of the CC, and identify molecular pathways critical for this process. This novel study will also provide avenues for deciphering mechanisms underlying abnormal CC formation implicated in functional deficits associated with ASD and other neurodevelopmental disorders. Our results will open new avenues to therapeutic approaches by targeting these molecular pathways for abnormal CC development.
The proposed study will test the hypothesis that Plexin-A4 plays an essential role in postnatal maintenance of callosal projections, abnormalities in which may contribute to the smaller corpus callosum in autism. The results will provide novel insights into as yet unknown mechanisms underlying developmental refinement of callosal projections, and their abnormalities in autism and other callosal disorders.
| Hashimoto-Torii, Kazue; Sasaki, Masanori; Chang, Yu-Wen et al. (2018) Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system. IBRO Rep 5:91-98 |
| Son, Alexander I; Opfermann, Justin D; McCue, Caroline et al. (2017) An Implantable Micro-Caged Device for Direct Local Delivery of Agents. Sci Rep 7:17624 |
