Biology subjects

Murray, G. C.

Publications and source records attributed to Murray, G. C..

3 recordsLinked to original sources

bioRxiv2025

A new mouse mutant with a discrete mutation in Pcdhgc5 reveals that the Protocadherin γC5 isoform is not essential for dendrite arborization in the cerebral cortex

There are [~]60 clustered protocadherin (cPcdh) isoforms expressed from three gene clusters (Pcdha, Pcdhb, Pcdhg) arrayed in tandem across nearly 1 Mb in mammals. cPcdhs are homophilic cell adhesion molecules (CAMs) critical for a host of neural developmental functions consistent with a role in cell-cell recognition. Indeed, isoforms make recognition modules in combination to generate recognition diversity far exceeding the [~]60 individual CAMs. However, there is also growing evidence for specialized functions for specific isoforms, particularly the C-type isoforms found at the 3 ends of the Pcdha cluster (C1 and C2) and at the 3 end of the Pcdhg cluster ({gamma}C3, {gamma}C4, and {gamma}C5). We have previously described unique roles for {gamma}C3 in dendrite arborization in the cerebral cortex and neural circuit formation in the spinal cord, as well as for {gamma}C4 in neuronal survival. Here we report a new mouse mutant specifically targeting the Pcdhgc5 exon encoding {gamma}C5. Unlike the rest of the Pcdhg cluster, expression of this isoform does not begin until postnatal stages of mouse development, increasing in the second week of life, suggesting specialized roles. We found significant expression changes in gene pathways involved in synaptic activity, learning and memory, and cognition. Despite this, we saw no major disruption in the cerebral cortex in neuronal organization, survival, dendritic arborization, or synaptic protein expression in these mutants. This new model will be an important tool for future studies delineating specific functions for {gamma}C5.

neuroscience↗

bioRxiv2023

Testing SIPA1L2 as a modifier of CMT1A using mouse models

Charcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validate SIPA1L2 as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion in SIPA1L2 and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction between Sipa1l2 deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement of Sipa1l2 in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions between Sipa1l2 deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.

genetics↗

bioRxiv2021

An allelic series of spontaneous mutations in Rorb cause a gait phenotype, retinal abnormalities, and transcriptomic changes relevant to human neurodevelopmental conditions

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic "high-stepper" or "duck-like" gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent (TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD. {blacksquare}Five mutant mice with a characteristic high-stepper gait phenotype have mutations in Rorb {blacksquare}These allelic series mutations manifest in a spectrum of anatomical and physiological abnormalities {blacksquare}Gene expression data suggest involvement of pathways related to neurodevelopmental disorders

genetics↗