Visual subcircuit-specific dysfunction and input-specific mispatterning in the superior colliculus of fragile X mice

Abstract Background Sensory processing deficits are frequently co-morbid with neurodevelopmental disorders. For example, patients with fragile X syndrome (FXS), caused by a silencing of the FMR1 gene, exhibit impairments in visual function specific to the dorsal system, which processes motion information. However, the developmental and circuit mechanisms underlying this deficit remain unclear. Recently, the superior colliculus (SC), a midbrain structure regulating head and eye movements, has emerged as a model for dissecting visual circuit development and function. Previous studies have demonstrated a critical role for activity-dependent processes in the development of visual circuitry in the SC. Based on the known role of the FMR1 gene product in activity-dependent synaptic plasticity, we explored the function and organization of visual circuits in the SC of a mouse model of FXS (Fmr1−/y). Methods We utilized in vivo extracellular electrophysiology in combination with computer-controlled visual stimuli to determine the receptive field properties of visual neurons in the SC of control and Fmr1−/y mice. In addition, we utilized anatomical tracing methods to assess the organization of visual inputs to the SC and along the retinogeniculocortical pathway. Results Receptive fields of visual neurons in the SC of Fmr1−/y mice were significantly larger than those found in control animals, though their shape and structure were unaffected. Further, selectivity for direction of movement was decreased, while selectivity to axis of movement was unchanged. Interestingly, axis-selective (AS) neurons exhibited a specific hyperexcitability in comparison to AS neurons in control SC and to direction-selective (DS) neurons in both control and Fmr1−/y SC. Anatomical tracings revealed that retinocollicular, retinogeniculate, and geniculocortical projections were normally organized in the absence of Fmr1. However, projections from primary visual cortex (V1) to the SC were poorly refined. Conclusions Fmr1 is required for the proper development of visual circuit organization and function in the SC. We find that visual dysfunction is heterogeneously manifested in a subcircuit-specific manner in Fmr1−/y mice, consistent with previous studies in human FXS patients. Further, we show a specific alteration of inputs to the SC from V1, but not the retina. Together, these data suggest that Fmr1 may function in distinct ways during the development of different visual subcircuits.https://deepblue.lib.umich.edu/bitstream/2027.42/144523/1/11689_2018_Article_9241.pd

Whole-Genome SNP Association in the Horse: Identification of a Deletion in Myosin Va Responsible for Lavender Foal Syndrome

Lavender Foal Syndrome (LFS) is a lethal inherited disease of horses with a suspected autosomal recessive mode of inheritance. LFS has been primarily diagnosed in a subgroup of the Arabian breed, the Egyptian Arabian horse. The condition is characterized by multiple neurological abnormalities and a dilute coat color. Candidate genes based on comparative phenotypes in mice and humans include the ras-associated protein RAB27a (RAB27A) and myosin Va (MYO5A). Here we report mapping of the locus responsible for LFS using a small set of 36 horses segregating for LFS. These horses were genotyped using a newly available single nucleotide polymorphism (SNP) chip containing 56,402 discriminatory elements. The whole genome scan identified an associated region containing these two functional candidate genes. Exon sequencing of the MYO5A gene from an affected foal revealed a single base deletion in exon 30 that changes the reading frame and introduces a premature stop codon. A PCR–based Restriction Fragment Length Polymorphism (PCR–RFLP) assay was designed and used to investigate the frequency of the mutant gene. All affected horses tested were homozygous for this mutation. Heterozygous carriers were detected in high frequency in families segregating for this trait, and the frequency of carriers in unrelated Egyptian Arabians was 10.3%. The mapping and discovery of the LFS mutation represents the first successful use of whole-genome SNP scanning in the horse for any trait. The RFLP assay can be used to assist breeders in avoiding carrier-to-carrier matings and thus in preventing the birth of affected foals

Novel Mechanisms for the Alteration of RET Receptor Tyrosine Kinase Signal Transduction.

Receptor tyrosine kinases (RTKs) are the second largest family of transmembrane receptors, and these proteins regulate numerous cellular processes including cell survival, metabolism, proliferation and differentiation. Mutations that affect the activity, abundance, cellular distribution or regulation of these receptors often leads to diseases such as cancer, making our understanding of the basic biology of these receptors, especially the regulation of their expression and signaling, critically important. One such RTK, RET, is a receptor for glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and has several functions in the developing embryo, including crucial roles in kidney morphogenesis, spermatogenesis and development of numerous neuronal populations. Regulation of RET through mechanisms such as intracellular trafficking, turnover and activation change the signaling capabilities of RET and have been well studied. Here I present two additional novel mechanisms of action of RET. In the first investigation, I explored the effects of novel 5’-alternative splicing on RET protein structure and function. These isoforms, which arise from exon skipping, are full-length RET proteins with deletions in the extracellular domain and are referred to as RETΔE3 and RETΔE345. I found that these isoforms differ from full-length RET in both their biochemical properties as well as their signaling capabilities. In the second study, I investigated the interaction of RET with p75, a pro-apoptotic protein that is a member of the tumor necrosis factor receptor (TNFR) superfamily. While I discovered that RET and p75 interact, and that this association is increased by the presence of pro-apoptotic stimuli in vitro, I identified a p75-independent role for RET in programmed cell death in the sympathetic nervous system during development in vivo. These data provide two novel mechanisms for the regulation of RET which, along with future studies, will further our understanding of RET biology under physiologic and pathologic conditions.PhDCellular and Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120720/1/ngab_1.pd