Makiou, A.-S. | bioRxiv Science

bioRxiv2026

Dyrk1a gene dosage controls bipolar cell development and retinal connectivity.

Mammalian retina development is governed by a core set of eye-field transcription factors that orchestrate tissue lamination and neuronal connectivity through tightly regulated genetic hierarchies. The LIM homeodomain gene Lhx2 functions as a master eye-field regulator and this study identifies Dyrk1a as a previously unrecognised effector of Lhx2-dependent programs during mouse retinal development. Conditional deletion of Dyrk1a in retinal progenitor cells led to increased apoptosis within the inner retina demonstrating a requirement for Dyrk1a in cell survival and lineage maintenance. Adult heterozygous mice exhibited dorsoventral reductions in bipolar cell number and indicated a gene-dosage-sensitive control of interneuron survival. Bipolar cell loss disrupted their mosaic organisation and resulted in diminished activity across both scotopic and photopic retinal pathways. Dyrk1a haploinsufficient mice also displayed pronounced disruption of inner plexiform layer stratification consistent with defective laminar targeting and synaptic partner integration. This study defines a gene-dosage-dependent mechanism through which transcriptional hierarchies regulate neuronal connectivity and function during mammalian retinal development.

developmental biology↗

bioRxiv2025

Novel Cln8 p.R24G mouse line replicates major clinical features of Northern epilepsy

RationaleNorthern epilepsy belongs to a group of genetically diverse lysosomal storage diseases, the neuronal ceroid lipofuscinoses (NCLs). A characteristic feature of NCL pathology is the accumulation of autofluorescent ceroid lipofuscin in the central nervous system. Northern epilepsy is a late-infantile-onset disease. Patients develop normally until 5-10 years old, when they first present with general tonic-clonic seizures, followed by progressive cognitive impairment and a decline in motor skills. Northern epilepsy is caused by a missense variant in CLN8, causing a p.R24G amino acid substitution. CLN8 deficiency has been studied traditionally using motor neuron degeneration (mnd) mice, which carry a spontaneous frame shift variant in the murine orthologue Cln8, which is not known to exist in humans. MethodsWe have generated the first Cln8 p.R24G mouse model (Cln8R24G) using CRISPR/Cas9. Phenotyping analysis of the mice was conducted using behavioral and histopathological studies focusing on the brain and retina. ResultsAt birth, Cln8R24G KI mice were viable and asymptomatic. As the mice aged, a progressive accumulation of autofluorescent ceroid lipofuscin containing the mitochondrial ATP synthase subunit C was evident in different brain regions and retinal layers. Health monitoring revealed that mutant mice developed progressive but mild motor symptoms around 7 months of age. Spontaneous epileptic seizures, like those observed in Northern epilepsy patients, were detected and recorded. An increase in FosB staining intensity, reflecting neuronal hyperactivity, was observed in hippocampal CA1-CA3 pyramidal and dentate granule cells and correlated well with the intensity of seizure activity. Neuroinflammation was evident at 4 months and increased dramatically with age, mainly in the thalamic VPN/VPL nuclei and moderately in the cortex. Neurodegeneration was most prominent in the VPN/VPL thalamic nuclei. ConclusionsWe have generated the Cln8R24G mouse model that genocopies, for the first time, the pathogenic CLN8 variant present in patients with Northern epilepsy. These mice phenocopy major clinical features of the human disease, including mild motor impairment and, unlike the mnd mice, spontaneous generalized tonic-clonic seizures. We hypothesize that our mouse model will open new possibilities for developing and testing targeted treatment options for Northern epilepsy and, more broadly, for early-onset neurodegenerative disorders associated with epilepsy.

neuroscience↗