Biology subjects

Zech, M.

Publications and source records attributed to Zech, M..

3 recordsLinked to original sources

bioRxiv2026

Kif2C safeguards radial glial integrity to prevent cortical malformation

Radial glial cells (RGCs) generate cortical neurons and guide radial neuronal migration, yet how microtubule (MT) regulators coordinate progenitor maintenance, mitotic fidelity, and cortical architecture remains unclear. Here, we identify the MT depolymerase Kif2C/MCAK as an essential regulator of RGC integrity with relevance to human neurodevelopmental disorders. Kif2C is enriched in developing cortical RGCs and localizes to radial fibers, basal endfeet, and mitotic structures. Acute Kif2C depletion in embryonic mouse cortices disrupts RG fiber organization, impairs neuronal migration, reduces the RGC pool, and induces mitotic defects, chromosome segregation errors, DNA damage, and cell-cycle arrest. Kif2C-deficient cortices further exhibit focal pial basement membrane disruption and neuronal overmigration, resulting in a cobblestone-like cortical malformation. We identify two individuals with neurodevelopmental disorders carrying rare deleterious KIF2C variants and show that a patient-derived truncating variant fails to rescue Kif2C-deficient cortical phenotypes, implicating KIF2C dysfunction in human neurodevelopmental disorders. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/726143v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@1970844org.highwire.dtl.DTLVardef@9fe29eorg.highwire.dtl.DTLVardef@d72ddcorg.highwire.dtl.DTLVardef@103f729_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure

Inosine 5 monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report identification of two additional affected individuals with missense variants in IMPDH2 and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation. Significance StatementPoint mutations in the human enzyme IMPDH2, a critical regulator of nucleotide biosynthesis, are linked to neurodevelopmental disorders, such as dystonia. Here, we report two additional IMPDH2 point mutants associated with similar disorders. We investigate the effects of each mutation on IMPDH2 structure and function in vitro and find that all mutations are gain of function, preventing allosteric regulation of IMPDH2 activity. We report high resolution structures of one variant and present a structure-based hypothesis for its dysregulation. This work provides a biochemical basis for understanding diseases caused by IMPDH2 mutation and lays a foundation for future therapeutic development.

biochemistry↗

bioRxiv2021

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen 3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3CTT mice showed a recessive dystonia-like phenotype. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3CTT mice have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3CTT mice was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control. SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.

neuroscience↗