Background: IGBP1/␣4 interacts with microtubule-associated MID1 to regulate PP2A within the mTOR pathway. Results: MID1 catalyzes the polyubiquitination and degradation of ␣4, demonstrating for the first time a mechanism for ␣4 regulation. Conclusion:The tandem RING-Bbox domains are required for ␣4 polyubiquitination and degradation. Significance: Ectopic overexpression of IGBP1/␣4 transforms cells. Ubiquitination of ␣4 impacts the stability and activity level of PP2A.

SUMMARY The hypothalamus integrates information required for the production of a variety of innate behaviors such as feeding, mating, aggression and predator avoidance. Despite an extensive knowledge of hypothalamic function, how embryonic genetic programs specify circuits that regulate these behaviors remains unknown. Here, we find that in the hypothalamus the developmentally regulated homeodomain-containing transcription factor Dbx1 is required for the generation of specific subclasses of neurons within the lateral hypothalamic area/zona incerta (LH) and the arcuate (Arc) nucleus. Consistent with this specific developmental role, Dbx1 hypothalamic-specific conditional-knockout mice display attenuated responses to predator odor and feeding stressors but do not display deficits in other innate behaviors such as mating or conspecific aggression. Thus, activity of a single developmentally regulated gene, Dbx1, is a shared requirement for the specification of hypothalamic nuclei governing a subset of innate behaviors.

Alterations in gene dosage due to copy-number variation (CNV) are associated with autism spectrum disorder (ASD), intellectual disability (ID) and other psychiatric disorders. The nervous system is so acutely sensitive to the dose of methyl-CpG-binding protein 2 (MeCP2) that even a two-fold change in MeCP2 protein level—either increased or decreased—results in distinct disorders with overlapping features including ID, autistic behavior and severe motor dysfunction. Rett syndrome is caused by loss-of-function mutations in MECP2, whereas duplications spanning the MECP2 locus result in MECP2 Duplication Syndrome (MDS) which accounts for ~1% of X-linked ID. Despite evidence from mouse models that restoring MeCP2 levels can reverse the course of disease, there are currently no FDA-approved therapies available to clinically modulate MeCP2 abundance. In this study we used a forward genetic screen against all known human kinases and phosphatases to identify druggable regulators of MeCP2 stability. Two putative modulators of MeCP2 levels, HIPK2 and protein phosphatase PP2A, were validated as stabilizers of MeCP2 in vivo. Further, pharmacological inhibition of PP2A in vivo reduced MeCP2 levels within the nervous system and rescued both overexpression and motor abnormalities in a mouse model of MDS. Our findings reveal potential therapeutic targets for treating disorders of altered MECP2 dosage and establish a potent strategy to identify druggable candidates for the broader category of neurologic disease resulting from CNVs.

Funding informationBlue Bird Circle, Houston Mutations in MECP2 are causative for Rett syndrome (RTT, OMIM 312750) in 95-97% of typical cases (Amir et al., 1999; Neul et al., 2008). In order to diagnose typical Rett syndrome, a patient must have undergone developmental regression after developing neurotypically in the first 6-18 months. Additional obligatory features are loss of acquired language, loss of purposeful hand skills, gait abnormalities (dyspraxia), and Rett-typical hand stereotypies such as hand-washing or hand-wringing (Neul et al., 2010). A diagnosis of atypical RTT is given if an individual presents with a period of regression followed by stabilization, at least 2 out of the 4 main criteria mentioned above, and at least 5 out of 11 supportive criteria (see Table 1 for RTT diagnostic criteria) (Neul et al., 2010).We present a 7-year-old female patient born at 39 weeks by emergent C-section due to rupture of membranes. Maternal age at time of birth was 30 years and paternal age was 27 years. There was no consanguinity. The patient has an older full sister (age 10) who is healthy and has developed normally. At birth, our patient weighed 3,402 g (69%ile) and measured 50.8 cm (82%ile) in length. Apgar scores at birth were both nine at 1 and 5 min. Immediate postnatal course was uneventful and she left the hospital at 4 days of life. The mother soon noticed a poor suck when breastfeeding and the patient was noted to have global neonatal hypotonia. For that reason, the patient has been receiving physiotherapy since infancy. She rolled over at 11 months and started walking at 23 months of age. At around 2 years she spoke five words and was also able to communicate using five to six gestures.Stereotypic hand movements in the form of tapping and clapping started when she was 2 years old, but she never developed handwringing or hand-washing stereotypies. By the age of 2.5 years the patient had acquired around 50 words, which were subsequently reduced to 6 words in a regression phase that lasted from the ages of 3 to 4.5 years. During this period, the patient became more withdrawn and grew more irritable. She also did not sleep through the night and often cried inconsolably. The mother also reports that her daughter previously had a pincer grasp, which regressed to a raking grip. Postregression the patient uses 5 words and communicates mostly with a PRC (Prentke Romich Company) communication device with which she reportedly expresses about 70 words. She maintains some purposeful hand use as she can hold a cup, uses utensils to feed herself, and communicates by pointing or touching the PRC device. Her hand use is apraxic. The patient can walk, climb stairs, and run. However, her gait is broad-based and she is clumsy. The patient has bruxism and high pain tolerance. She has infrequent breath-holding episodes, of the type that