Biology subjects

Arbogast, T.

Publications and source records attributed to Arbogast, T..

4 recordsLinked to original sources

bioRxiv2026

Evolutionary rewiring of the DNM2 proline-rich domain drives lineage-specific constraints in erythropoiesis

Dynamin-2 (DNM2) is a ubiquitously expressed GTPase essential for membrane trafficking, yet how its evolution shapes tissue-specific functions remains unclear. Here, we generated a humanized mouse model in which murine Dnm2 is fully replaced by human DNM2. Human DNM2 rescues the embryonic lethality of Dnm2 deletion but cannot sustain postnatal hematopoiesis, leading to fatal hemolytic anemia, erythroblast maturation arrest, reticulocytosis, and macrothrombocytosis. The defect emerges selectively during postnatal bone marrow erythropoiesis and is associated with impaired transferrin receptor turnover, despite normal fetal liver hematopoiesis. Comparative proteomics reveals extensive species-specific rewiring of the DNM2 proline-rich domain (PRD) interactome, with GRB2 as the sole conserved partner. Dnm2 haploinsufficiency phenocopies the erythroid defect with reduced severity, indicating a dosage-sensitive loss-of-function mechanism. These findings identify PRDs as rapidly evolving context-dependent adaptors that tune ubiquitous proteins to tissue-specific demands, and highlight regulatory domains compatibility as a key consideration for humanized models and gene-replacement strategies.

genetics↗

bioRxiv2025

DNM2-CMT neuropathy stems from disrupted Schwann cell function and shows limited therapeutic reversibility

Dominant loss-of-function mutations in DNM2 cause Charcot-Marie-Tooth (CMT) neuropathy characterized by sensory and motor deficits associated with myelin and/or axonal abnormalities and muscle atrophy. Increasing DNM2 activity from embryogenesis has been reported to ameliorate neuromuscular phenotypes in the Dnm2K562E/+ CMT mouse; however, this model displays predominantly muscle pathology and limited nerve involvement, precluding rigorous evaluation of neuropathic mechanisms and potential therapies. Here, we performed comprehensive behavioral, electrophysiological, histological and molecular analyses to characterize the Dnm2K562E/SC- mouse, which combines systemic heterozygosity for the common K562E mutation together with Schwann cell (SC)-specific deletion of wild-type Dnm2. This model faithfully reproduces key clinical and pathological features of DNM2-CMT, including motor deficits, reduced general force and coordination, and severe sensory and motor conduction deficits associated with axonal loss, demyelination, and inflammation. Mechanistically, we delineate a coherent pathological sequence that explains the profound functional deficits. In particular, a downregulation of the transcription factor EGR2, a master regulator of myelin gene expression, and of the myelin protein MPZ correlates with demyelination. To evaluate the therapeutic potential of DNM2 supplementation, post-symptomatic intrathecal delivery of AAV9-DNM2 driven by the Schwann cell-specific MPZ promoter was performed at 4 weeks. Although DNM2 expression increased in peripheral nerves ([~]1.9-fold), no significant improvements were observed across behavioural, electrophysiological, structural, or molecular parameters. Together, these findings establish the Dnm2K562E/SC- mouse as a robust preclinical model, recapitulating key features of DNM2-CMT, and provides crucial insight into the biological and temporal constraints that must guide future therapeutic strategies for DNM2-CMT.

neuroscience↗

bioRxiv2019

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

Whereas genome-wide association studies (GWAS) allowed identifying thousands of associations between variants and traits, their success rate in pinpointing causal genes has been disproportionately low. Here, we integrate biobank-scale phenotype data from carriers of a rare copy-number variant (CNV), Mendelian randomization and animal modeling to identify causative genes in a GWAS locus for age at menarche (AaM). We show that the dosage of the 16p11.2 BP4-BP5 interval is correlated positively with AaM in the UK and Estonian biobanks and 16p11.2 clinical cohorts, with a directionally consistent trend for pubertal onset in males. These correlations parallel an increase in reproductive tract disorders in both sexes. In support of these observations, 16p11.2 mouse models display perturbed pubertal onset and structurally altered reproductive organs that track with CNV dose. Further, we report a negative correlation between the 16p11.2 dosage and relative hypothalamic volume in both humans and mice, intimating a perturbation in the gonadotropin-releasing hormone (GnRH) axis. Two independent lines of evidence identified candidate causal genes for AaM; Mendelian randomization and agnostic dosage modulation of each 16p11.2 gene in zebrafish gnrh3:egfp models. ASPHD1, expressed predominantly in brain and pituitary gland, emerged as a major phenotype driver; and it is subject to modulation by KCTD13 to exacerbate GnRH neuron phenotype. Together, our data highlight the power of an interdisciplinary approach to elucidate disease etiologies underlying complex traits.

genomics↗

bioRxiv2019

Oligogenic effects of 16p11.2 copy number variation on craniofacial development

A copy number variant (CNV) of 16p11.2, which encompasses 30 genes, is associated with developmental and psychiatric disorders, head size and body mass. The genetic mechanisms that underlie these associations are not understood. To elucidate the effects of genes on development, we exploited the quantitative effects of CNV on craniofacial structure in humans and model organisms. We show that reciprocal deletion and duplication of 16p11.2 have characteristic "mirror" effects on craniofacial features that are conserved in human, rat and mouse. By testing gene dosage effects on the shape of the mandible in zebrafish, we show that the distribution of effects for all individual genes is consistent with that of the CNV, and some combinations have non-additive effects. Our results suggest that, at minimum, one third of genes within the 16p11.2 region influence craniofacial development, and the facial gestalt of each CNV represents a product of 30 dosage effects. HighlightsO_LIReciprocal CNVs of 16p11.2 have mirror effects on craniofacial structure. Copy number is associated with a positive effect on nasal and mandibular regions and a negative effect on frontal regions of the face. C_LIO_LIEffects of CNV on craniofacial development in human are well conserved in rat and mouse models of 16p11.2 deletion and duplication. C_LIO_LI7/30 genes each independently have significant effects on the shape of the mandible in zebrafish; these include SPN, C16orf54, SEZ6L2, ASPHD1, TAOK2, INO80E and FAM57B. Others (MAPK3, MVP, KCTD13) have detectable effects only in combination. C_LIO_LIOverexpression of 30 genes individually showed a distribution of effects that was skewed in the same direction as that of the full duplication, suggesting that specific facial features represent the net of all individual effects combined. C_LI

genetics↗