Limbs develop using a common genetic programme despite widely differing morphologies. This
programme is modulated by limb-restricted regulators such as hindlimb (HL) transcription
factors Pitx1 and Tbx4 and the forelimb (FL) Tbx5. Both Tbx factors have been implicated in
limb patterning and growth, but their relative activities and underlying mechanisms remain
unclear. In this paper, we show that Tbx4 and Tbx5 harbour conserved and divergent
transcriptional regulatory domains that account for their roles in limb development. In
particular, both factors share an activator domain and the ability to stimulate limb growth.
However, we find that Tbx4 is the primary effector of HL identity for both skeletal and
muscle development; this activity relies on a repressor domain that is inactivated by a
human TBX4 small-patella syndrome mutation. We propose that limb identity is largely
achieved by default in FL, whereas a specific repressor activity unique to Tbx4 determines
HL identity.
The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.
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