Biology subjects

Goldowitz, D.

Publications and source records attributed to Goldowitz, D..

7 recordsLinked to original sources

bioRxiv2026

Brain structural and genetic correlates of motor coordination and learning behaviours: modelling developmental coordination disorder

Developmental coordination disorder (DCD) is a common neurodevelopmental condition characterized by impaired motor coordination and learning, yet its neurobiological and genetic bases remain poorly understood. Here, we leverage the BXD recombinant inbred mouse panel to model the polygenic architecture of DCD and link behaviour, brain structure, and genotype. High-resolution ex vivo MRI across 14 strains revealed that DCD-like mice have modestly reduced total brain volume, with a distinct neuroanatomical profile characterized by enlarged cortical regions alongside reduced cerebellar, thalamic, and other subcortical volumes. These structural differences closely mirror findings reported in human DCD. Across strains, variation in brain structure strongly correlated with motor behaviours, with coordinated patterns linking increased cortical and decreased subcortical volumes to poorer motor coordination, while more focal associations were observed for motor learning. Multivariate analysis identified a dominant brain-behaviour axis capturing this cortical-subcortical trade-off. Quantitative trait locus (QTL) mapping revealed multiple loci influencing regional brain volumes, including a prominent locus on chromosome 12 regulating cerebellar structures, but did not identify single loci driving the main multivariate brain-behaviour relationships, consistent with a distributed genetic architecture. Together, these findings demonstrate that DCD-like motor impairments arise from coordinated alterations across distributed brain systems under polygenic control. This work establishes a translational framework linking genetic variation to brain organization and motor function, and suggests that DCD reflects the extreme of a continuous spectrum of neurobiological variation rather than a discrete condition.

neuroscience↗

bioRxiv2026

Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation

Mouse meander tail (mea) mutations produce kinked tails and selective malformation of the cerebellum anterior compartment. The anterior cerebellum defects are cell autonomous with respect to granule cell precursors, but the molecular basis has not been known. Myb-like, SWIRM, and MPN domain containing protein 1 (MYSM1) is a chromatin-associated deubiquitinase that promotes gene expression by removing monoubiquitin from histone H2A, among other targets. Loss of MYSM1 function in mice or humans results in bone marrow failure with defective maturation of B cell lineages. Here we show that extant mea alleles have mutations in Mysm1 and cause both neurological and hematological phenotypes, as do new non-complementing endonuclease-mediated mutations. Multimodal single-nucleus assays show Mysm1 effects on gene expression in several lineages and on the proportion of granule cell precursors by E14.5. Intriguingly, Mysm1 orthologs have been independently lost in several animal and fungal lineages, including yeast, flies, and nematodes. These results unite previously disconnected literature and demonstrate a requirement for MYSM1 activity in compartment-specific development of the cerebellum and suggest potential for compensatory pathways. Significance StatementPerturbations to core regulatory machinery often produce pleiotropic effects and even intensively studied systems can have significant phenotypic effects that were not assessed in models developed for a different purpose. Here we show that classical meander tail mice, characterized by ankylosing spondylitis in tail vertebrae and a cerebellum malformation that defined the anterior-posterior compartment boundary, have mutations in Mysm1, encoding a histone 2A deubiquitinase. We show pigmentation defects and hematopoietic abnormalities that model human disease. While Mysm1 mutations change gene expression patterns in many cerebellar cell types, they selectively decrease the proportion of granule cell lineages. Recurrent loss of Mysm1 orthologs across fungal and animal phylogenies suggests the potential for bypass mechanisms.

genetics↗

bioRxiv2023

Msx genes delineate a novel molecular map of the developing cerebellar neuroepithelium.

In the early cerebellar primordium, there are two progenitor zones, the ventricular zone (VZ) residing atop the IVth ventricle and the rhombic lip (RL) at the lateral edges of the developing cerebellum. These zones give rise to the several cell types that form the GABAergic and glutamatergic populations of the adult cerebellum, respectively. Recently, an understanding of the molecular compartmentation of these zones has emerged. The Msx genes are a family of three transcription factors that are expressed downstream of Bone Morphogenetic Protein (BMP) signaling in these zones. Using fluorescent RNA in situ hybridization, we have characterized the Msx (Msh Homeobox) genes and demonstrated that their spatiotemporal pattern segregates specific regions in the progenitor regions. Msx1 and Msx2 are compartmentalized within the rhombic lip (RL), while Msx3 is localized within the ventricular zone (VZ). The relationship of the Msx genes with an early marker of the glutamatergic lineage, Atoh1, was examined in Atoh1-null mice and it was found that the expression of Msx genes persisted. Importantly, Msx1 and Msx3 expressions expanded in response to the elimination of Atoh1. These results point to early markers of cerebellar progenitor zones and more importantly to an updated view of the molecular parcellation of the RL with respect to the canonical marker of the RL, Atoh1.

developmental biology↗

bioRxiv2022

Investigating mouse motor coordination using quantitative trait locus analysis to model the genetic underpinnings of developmental coordination disorder

The fundamental skills for motor coordination and motor control emerge through development, from infancy to late childhood years. Neurodevelopmental disorders such as Developmental Coordination Disorder (DCD) lead to impaired acquisition of motor skills. This study investigated motor behaviors that reflect the core symptoms of human DCD through the use of BXD recombinant inbred lines of mice that are known to have divergent phenotypes in many behavioral traits, including motor activity. We sought to correlate behavior in basic motor control tasks with the known genotypes of these reference populations of mice using quantitative trait locus (QTL) mapping. We used twelve BXD lines with an average of 16 mice per group to assess the onset of reflexes during the early neonatal stage of life and differences in motor coordination using the open field, rotarod, and gait analyses during the adolescent/young adulthood period. Results indicated significant variability between lines in as to when neonatal reflexes appeared as well as significant line differences for all measures of motor coordination. Five lines (BXD15, BXD27, BXD28, BXD75, and BXD86) struggled with sensorimotor coordination as seen in gait analysis, rotarod, and open field, similar to human presentation of DCD. We identified three significant quantitative trait loci for gait on proximal Chr 3, Chr 4 and distal Chr 6. Based on expression, function, and polymorphism within the mapped QTL intervals, 7 candidate genes (Gpr63, Spata5, Trpc3, Cntn6, Chl1, Grm7 and Ogg1) emerged. This study offers new insights into mouse motor behavior which promises to be a first murine model to explore the genetics and neural correlates of DCD.

neuroscience↗

bioRxiv2022

Developmental Coordination Disorder: What Can We Learn From Recombinant Inbred Mice Using Motor Learning Tasks and Quantitative Trait Locus Analysis

Developmental Coordination Disorder (DCD) is a motor skills disorder that affects 5-6% of all school-aged children. There is an indication that DCD has an underlying genetic component due to its high heritability. Therefore, we we have explored the use of a recombinant inbred family of mice known as the BXD panel to understand the genetic basis of complex traits (i.e., motor learning) through identification of Quantitative Trait Loci (QTLs). The overall aim of this study was to utilize the QTL approach to evaluate the genome-to-phenome correlation in BXD strains of mice in order to to better understanding the human presentation of DCD. Results in this current study indicate there is a spectrum of motor learning in the pre-selected BXD strains of mice with a spectrum between high and low learning capabilities. Five lines - BXD15, BXD27, BXD28, BXD75, and BXD86 - exhibited the most DCD-like phenotype, when compared to other BXD lines of interest. The results indicate that BXD15 and BXD75 struggled primarily with gross motor skills, BXD28 primarily had difficulties with fine motor skills, and BXD27 and BXD28 lines struggled with both fine and gross motor skills. The functional roles of significant QTL genes were assessed in relation to DCD-like behavior. Only Rab3a (Ras-related protein Rab-3A) emerged as a best candidate gene for the horizontal ladder rung task. This gene is found to be associated with brain and skeletal muscle development. This is the first study to specifically examine the genetic linkage of DCD using BXD lines of mice.

neuroscience↗

bioRxiv2021

Temporal analysis of enhancers during mouse brain development reveals dynamic regulatory function and identifies novel regulators of cerebellar development.

In this study, we identified active enhancers in the mouse cerebellum at embryonic and postnatal stages establishing the first catalog of enhancers active during embryonic cerebellum development. The majority of cerebellar enhancers have dynamic activity between embryonic and postnatal development. Cerebellar enhancers were enriched for neural transcription factor binding sites with temporally specific expression. Putative gene targets displayed spatially restricted expression patterns, indicating cell-type specific expression regulation. Functional analysis of target genes indicated that enhancers regulate processes spanning several developmental epochs such as specification, differentiation and maturation. We use these analyses to discover one novel regulator and one novel marker of cerebellar development: Bhlhe22 and Pax3, respectively. We identified an enrichment of de novo mutations and variants associated with autism spectrum disorder in cerebellar enhancers. Our study provides insight into the dynamics of gene expression regulation by enhancers in the developing brain and delivers a rich resource of novel gene-enhancer associations providing a basis for future in-depth studies in the cerebellum.

neuroscience↗

bioRxiv2020

The transcription factor Pou3f1 provides a new map to the glutamatergic neurons of the cerebellar nuclei

Pou3f1 is a transcription factor involved in early neural differentiation. Cap Analysis Gene Expression (5-CAGE) analysis reveals that Pou3f1 transcript is highly enriched in the developing cerebellum. Between embryonic (E) days E10.5 and E12.5, Pou3f1 expression is present prominently along the subpial stream (SS), suggesting that Pou3f1+ cells are glutamatergic cerebellar nuclear (CN) neurons. This finding was confirmed by immunofluorescent (IF) co-labeling of Pou3f1 and Atoh1, the master regulator of cells from the rhombic lip (RL) that are destined for neurons of the glutamatergic lineage, as well as in Atoh1-null tissues, in which Pou3f1 expression is absent. Interestingly, the expression of Pax6, another key molecule for CN neuron survival, does not co-localize with that of Pou3f1. In the Pax6-null Small Eye (Sey) mutant, which is characterized by a loss of many glutamatergic CN neurons, Pou3f1+ CN neurons are still present. Furthermore, Pou3f1-labeled cells do not co-express Tbr1, a well-established marker of glutamatergic CN neurons. These results highlight that Pou3f1+ cells are a distinct and previously unrecognized subtype of glutamatergic CN neurons that do not have the "canonical" sequence of Atoh1[->]Pax6[->]Tbr1 expressions. Instead, they express Atoh1, Pou3f1, and other markers of CN neurons, Brn2 and Irx3. These findings illustrate that glutamatergic CN neurons that arise from the RL are composed of molecularly heterogeneous subpopulations that are determined by at least two distinct transcriptional programs. Significance StatementThe present work has identified Pou3f1 as a marker for a previously unidentified subtype of glutamatergic cerebellar nuclear neurons, the principal output neurons of the cerebellum. The classical model of glutamatergic CN neurons development follows the sequential expression of transcription factors Atoh1[->]Pax6[->]Tbr1. However, we found that the development of Pou3f1+ neurons requires Atoh1 but not Pax6. Moreover, Pou3f1+ neurons do not express Tbr1, but instead express two other transcription factors, Brn2 and Irx3. Anatomically, Pou3f1+ CN neurons populate the interposed and dentate nuclei, while the Tbr1+ CN neurons populate the fastigial nucleus. These findings reveal the heterogeneity of CN neuron populations and the diversity of molecular programming that lead to different CN neuron subtypes.

neuroscience↗