Anat Shmueli

Radial neuronal migration is key in structuring the layered cortex. Here we studied the role of MARK2/Par-1 in this process. The dual name stands for the MAP/microtubule affinity-regulating kinase 2 (MARK2) and the known polarity kinase 1 (Par-1). Reduced MARK2 levels using in utero electroporation resulted in multipolar neurons stalled at the intermediate zone border. Reintroduction of the wild-type kinase postmitotically improved neuronal migration. Our results indicated that reduction in MARK2 affected centrosomal dynamics in migrating neurons of the cerebral cortex. Increased MARK2 has been shown to destabilize microtubules, and here we show for the first time that reduced MARK2 stabilized microtubules in primary cultured neurons. Kinase-independent activity permitted multipolar-to-bipolar transition but did not restore proper migration. Increased MARK2 levels resulted in a different phenotype, which is loss of neuronal polarity. MARK2 kinase activity reduction hindered migration in the developing brain, which was rescued by increasing kinase activity. Our results stress the necessity of maintaining dynamic microtubules for proper neuronal migration. Furthermore, the exact requirements for MARK2 and its kinase activity vary during the course of neuronal migration. Collectively, our results stress the requirements for the different roles of MARK2 during neuronal migration.

OBJECTIVE: To identify risk factors for mediolateral episiotomy, and evaluate the risk of obstetrical anal sphincter injury (OASI) among women with an episiotomy. METHODS: A retrospective cohort study of all singletons vaginal deliveries at term between 2007 and 2014. Spontaneous and operative vaginal deliveries were compared separately, as well as nulliparous and multiparous women. RESULTS: Overall, 41,347 women were included in the spontaneous vaginal delivery group: 12,585 (30.4%) nulliparous and 28,762 (69.6%) multiparous women. Risk factors for episiotomy (nulliparous) were maternal age (aOR 0.98), gestational age (GA, aOR 1.07), regional analgesia (RA, aOR 1.18), labor induction (aOR 1.17), meconium (aOR 1.37) and birth weight (BW, aOR 1.04). Episiotomy was associated with PPH (aOR 1.49). Among multiparous, risk factors were maternal age (aOR 1.04), previous vaginal delivery (aOR 0.38), GA (aOR 1.06), RA (aOR 1.22), meconium (aOR 1.22) and BW (aOR 1.05). Episiotomy was associated with 3rd degree perineal tear (aOR 2.26, 95% CI 1.03-4.97). Only birth weight (nulliparous) and previous vaginal deliveries (multiparous) were contributors for episiotomy in the OVD group. CONCLUSION: Several risk factors for mediolateral episiotomy exist. Episiotomy does not protect nulliparous women, and may be associated with an increased risk for multiparous, for OASI. Therefore, the practice of routine episiotomy should be abandoned, and the practice of selective episiotomy reconsidered.

The reward system is a collection of circuits that reinforce behaviors necessary for survival [1Kelley A.E. Berridge K.C. The neuroscience of natural rewards: relevance to addictive drugs.J. Neurosci. 2002; 22: 3306-3311Crossref PubMed Google Scholar, 2Edwards S. Koob G.F. Neurobiology of dysregulated motivational systems in drug addiction.Future Neurol. 2010; 5: 393-401Crossref PubMed Scopus (115) Google Scholar]. Given the importance of reproduction for survival, actions that promote successful mating induce pleasurable feeling and are positively reinforced [3Tenk C.M. Wilson H. Zhang Q. Pitchers K.K. Coolen L.M. Sexual reward in male rats: effects of sexual experience on conditioned place preferences associated with ejaculation and intromissions.Horm. Behav. 2009; 55: 93-97Crossref PubMed Scopus (100) Google Scholar, 4Paredes R.G. Evaluating the neurobiology of sexual reward.ILAR J. 2009; 50: 15-27Crossref PubMed Scopus (72) Google Scholar]. This principle is conserved in Drosophila, where successful copulation is naturally rewarding to male flies, induces long-term appetitive memories [5Shohat-Ophir G. Kaun K.R. Azanchi R. Mohammed H. Heberlein U. Sexual deprivation increases ethanol intake in Drosophila.Science. 2012; 335: 1351-1355Crossref PubMed Scopus (137) Google Scholar], increases brain levels of neuropeptide F (NPF, the fly homolog of neuropeptide Y), and prevents ethanol, known otherwise as rewarding to flies [6Devineni A.V. Heberlein U. Preferential ethanol consumption in Drosophila models features of addiction.Curr. Biol. 2009; 19: 2126-2132Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 7Kaun K.R. Azanchi R. Maung Z. Hirsh J. Heberlein U. A Drosophila model for alcohol reward.Nat. Neurosci. 2011; 14: 612-619Crossref PubMed Scopus (161) Google Scholar], from being rewarding [5Shohat-Ophir G. Kaun K.R. Azanchi R. Mohammed H. Heberlein U. Sexual deprivation increases ethanol intake in Drosophila.Science. 2012; 335: 1351-1355Crossref PubMed Scopus (137) Google Scholar]. It is not clear which of the multiple sensory and motor responses performed during mating induces perception of reward. Sexual interactions with female flies that do not reach copulation are not sufficient to reduce ethanol consumption [5Shohat-Ophir G. Kaun K.R. Azanchi R. Mohammed H. Heberlein U. Sexual deprivation increases ethanol intake in Drosophila.Science. 2012; 335: 1351-1355Crossref PubMed Scopus (137) Google Scholar], suggesting that only successful mating encounters are rewarding. Here, we uncoupled the initial steps of mating from its final steps and tested the ability of ejaculation to mimic the rewarding value of full copulation. We induced ejaculation by activating neurons that express the neuropeptide corazonin (CRZ) [8Tayler T.D. Pacheco D.A. Hergarden A.C. Murthy M. Anderson D.J. A neuropeptide circuit that coordinates sperm transfer and copulation duration in Drosophila.Proc. Natl. Acad. Sci. USA. 2012; 109: 20697-20702Crossref PubMed Scopus (89) Google Scholar] and subsequently measured different aspects of reward. We show that activating Crz-expressing neurons is rewarding to male flies, as they choose to reside in a zone that triggers optogenetic stimulation of Crz neurons and display conditioned preference for an odor paired with the activation. Reminiscent of successful mating, repeated activation of Crz neurons increases npf levels and reduces ethanol consumption. Our results demonstrate that ejaculation stimulated by Crz/Crz-receptor signaling serves as an essential part of the mating reward mechanism in Drosophila.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI1NWRhYzVmMDMwZWIwNDU2OWM5OTdlYzJiOTUxZTUwMiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3NjYyMDI0fQ.lFluPLjQVsI4e5rYXsW9-6Hkaqs6RW18ZWu5YE2N7VoE4_5VL8AU_02Vlt4MNyJj0QAdQ2NAJLXpg7xiVS21WpQQMCxaHCSBf6lW-u9JH5HRqIki8Swsv9E3K2IFuKeUJV5-7Ucl7LVK8PprVg_m96mjTqEuMaXsyGQ763gyThI1hIH-S5VrI3SuMhgL4ccRXHrzQQ8KKO-o4MAPnIGog2ovHWWEQGkJ2zl8ClYivjWlWb_lgCeet-As0wI4t5B0q-67CBXcGTNg9li7wetzLcO-WskS_k7ctk7tQ2wp-94MXBP7UsYwwRxbUxQrGhhRyA3eRIVxUkeyXvYc5EPtvA(mp4, (34.5 MB) Download video

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is a ubiquitous mechanism that generates transcriptomic diversity. This process is particularly important for proper neuronal function; however, little is known about how RNA editing is dynamically regulated between the many functionally distinct neuronal populations of the brain. Here, we present a spatial RNA editing map in the Drosophila brain and show that different neuronal populations possess distinct RNA editing signatures. After purifying and sequencing RNA from genetically marked groups of neuronal nuclei, we identified a large number of editing sites and compared editing levels in hundreds of transcripts across nine functionally different neuronal populations. We found distinct editing repertoires for each population, including sites in repeat regions of the transcriptome and differential editing in highly conserved and likely functional regions of transcripts that encode essential neuronal genes. These changes are site-specific and not driven by changes in Adar expression, suggesting a complex, targeted regulation of editing levels in key transcripts. This fine-tuning of the transcriptome between different neurons by RNA editing may account for functional differences between distinct populations in the brain.