Gain-of function mutations in some genes underlie neurodegenerative conditions whereas loss-of-function mutations have distinct phenotypes. Such appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain-of-function of the complex leads to neurodegeneration, but ATXIN1-CIC is also essential for survival. We set out to understand the functions of ATXN1-CIC in the developing forebrain and found that losing the complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper layer cortical neurons. We also found that CIC modulates social interactions in the hypothalamus and medial amygdala. Informed by these neurobehavioral features in mouse mutants, we identified five patients with de novo heterozygous truncating mutations in CIC that share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

SUMMARY Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger Complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of Sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups. We found that one-third of mice lacking Nalcn in excitatory preBötC neurons died soon after birth; surviving mice developed apneas in adulthood. Interestingly, in both preBötC and RTN neurons, the Nalcn current influences the resting membrane potential, contributes to maintenance of stable network activity, and mediates modulatory responses to the neuropeptide substance P. These findings reveal Nalcn’s specific role in both rhythmic stability and responsiveness to neuropeptides within the respiratory network.

Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atoh1's bHLH domain Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background () exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearing loss. We also found that heterozygous mice of both sexes () have adult-onset deafness. These data indicate that different cell types have different degrees of vulnerability to loss of Atoh1 function and that hypomorphic alleles should be considered in human hearing loss. The discovery that Atonal homolog 1 (Atoh1) governs the development of the sensory hair cells in the inner ear led to therapeutic efforts to restore these cells in cases of human deafness. Because prior studies of -heterozygous mice did not examine or report on hearing loss in mature animals, it has not been clinical practice to sequence in people with deafness. Here, in seeking to understand how phosphorylation of Atoh1 modulates its effects, we discovered that inner ear hair cells are much more vulnerable to loss of Atoh1 function than other Atoh1-positive cell types and that heterozygous mice actually develop hearing loss late in life. This opens up the possibility that missense mutations in could increase human vulnerability to loss of hair cells because of aging or trauma.