Mice with Sox5 inactivation in the Emx1 lineage as a model for the human Lamb-Shaffer neurodevelopmental syndrome.

Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder caused by variants that inactivate one SOX5 allele and thus reveal human SOX5 haploinsufficiency in higher-order brain functions. SOX5 encodes an SRY-related transcription factor highly expressed in cortical deep-layer excitatory neurons. Sox5-/- mice were previously shown to die at birth with severely impaired differentiation of these cells, whereas Sox5+/- mice appeared normal throughout life but were not investigated for neurological defects. We here asked whether these mice and mice with Emx1Cre-mediated inactivation of Sox5 in the progenitors of cortical and hippocampal excitatory neurons and glia exhibited LAMSHF-like behaviors. Neocortical neuron defects were equally severe in Sox5-/- and Sox5fl/flEmx1Cre/+ mice and were marginal in Sox5+/- and Sox5fl/+Emx1Cre/+ mice. Sox5fl/flEmx1Cre/+ mice survived birth but failed to thrive around weaning, unless given a nutritious gel complement. Behavior tests revealed motor performance deficits, reduced anxiety, impaired learning and memory skills, and autistic-like behaviors in Sox5fl/flEmx1Cre/+ mice and minor changes in Sox5+/- and Sox5fl/+Emx1Cre/+ mice. Electroencephalography findings were consistent with a mild, diffuse alteration of the cortex organization in homozygous mutants. Thus, while the abnormal features of Sox5fl/flEmx1Cre/+ mice evoked LAMSHF, global and conditional heterozygous mutants exhibited mild or no deficiencies. We conclude that mouse Sox5 may not be as haploinsufficient as human SOX5 in facilitating achievement of higher-order functions and that mice with homozygous loss of Sox5 in the Emx1 lineage are a suitable model to further investigate the LAMSHF-related functions of SOX5 and to preclinically test candidate therapies for LAMSHF individuals.