An allelic series of spontaneous mutations in Rorb cause a gait phenotype, retinal abnormalities, and transcriptomic changes relevant to human neurodevelopmental conditions

Abstract

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic high-stepper or duck-like gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent(TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD.

The developmental timing of spinal touch processing alterations and its relation to ASD-associated behaviors in mouse models

“…Thus, Nlgn2 and Rorb may function within a common feedforward inhibition pathway in the mature dorsal horn that regulates behavioral responses to touch after a critical time window of perinatal development, during which tactile signals shape the central circuits governing non-tactile ASD comorbidities 12 . Indeed, Nlgn2 and Rorb mutant animals exhibit normal anxiety-like and social behaviors in adulthood, although it is possible that these animals may exhibit behavioral alterations not examined here or in prior studies 35,44 . Taken together, we propose that the differences in the developmental timing of function of ASD-associated genes that act within the same circuitry, for example, Gabrb3, Mecp2, Nlgn2, and Rorb in the DRG sensory neuron/dorsal horn circuitry, help to explain the heterogeneity of behavioral outcomes observed across ASD mouse models.…”

“…The activity of Rorb-expressing interneurons is required for normal tactile and sensorimotor function 41,42 . To investigate the role of the Rorb gene in ASD-associated behaviors, we tested animals with a pathogenic mutation arising at the Rorb locus (Rorb h1 ) 43,44 . As observed in Gabrb3 +/-, Mecp2 -/y , and Nlgn2 +/animals, Rorb h1/+ mice exhibited enhanced tactile sensitivity in the tactile PPI assay, although Rorb h1/+ mice did not have enhanced reactivity to a gentle air puff alone (Fig.…”