JNK signaling is required for proper tangential migration and laminar allocation of cortical interneurons.

The precise migration of cortical interneurons is essential for the formation and function of cortical circuits, and disruptions to this key developmental process are implicated in the etiology of complex neurodevelopmental disorders, including schizophrenia, autism and epilepsy. We have recently identified the Jun N-terminal kinase (JNK) pathway as an important mediator of cortical interneuron migration in mice, regulating the proper timing of interneuron arrival into the cortical rudiment. In the current study, we demonstrate a vital role for JNK signaling at later stages of corticogenesis, when interneurons transition from tangential to radial modes of migration. Pharmacological inhibition of JNK signaling in ex vivo slice cultures caused cortical interneurons to rapidly depart from migratory streams and prematurely enter the cortical plate. Similarly, genetic loss of JNK function led to precocious stream departure ex vivo, and stream disruption, morphological changes and abnormal allocation of cortical interneurons in vivo These data suggest that JNK signaling facilitates the tangential migration and laminar deposition of cortical interneurons, and further implicates the JNK pathway as an important regulator of cortical development.

Early construction of the thalamocortical axon pathway requires c-Jun N-terminal kinase signaling within the ventral forebrain.

BACKGROUND: Thalamocortical connectivity is essential for normal brain function. This important pathway is established during development, when thalamic axons extend a long distance through the forebrain before reaching the cerebral cortex. In this study, we identify a novel role for the c-Jun N-terminal kinase (JNK) signaling pathway in guiding thalamocortical axons through intermediate target territories. RESULTS: Complete genetic removal of JNK signaling from the Distal-less 5/6 (Dlx5/6) domain in mice prevents thalamocortical axons from crossing the diencephalon-telencephalon boundary (DTB) and the internal capsule fails to form. Ventral telencephalic cells critical for thalamocortical axon extensions including corridor and guidepost neurons are also disrupted. In addition, corticothalamic, striatonigral, and nigrostriatal axons fail to cross the DTB. Analyses of different JNK mutants demonstrate that thalamocortical axon pathfinding has a non-autonomous requirement for JNK signaling. CONCLUSIONS: We conclude that JNK signaling within the Dlx5/6 territory enables the construction of major axonal pathways in the developing forebrain. Further exploration of this intermediate axon guidance territory is needed to uncover mechanisms of axonal pathfinding during normal brain development and to elucidate how this vital process may be compromised in neurodevelopmental disorders.

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice.

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

Preoperative and early adjuvant weight loss medications in bariatric surgery patients with body mass index over 60 or suboptimal initial response to surgery.

BACKGROUND: Few studies have examined the adjuvant use of antiobesity medications with surgery, especially in the pre- and early postoperative periods. OBJECTIVE: Evaluate the impact of adjuvant pharmacotherapy on bariatric surgery outcomes. SETTING: University hospital, United States. METHODS: A retrospective chart review of patients receiving adjuvant pharmacotherapy for obesity treatment and bariatric surgery. Patients received pharmacotherapy either preoperatively if their body mass index was >60, or in the first or second postoperative years for suboptimal weight loss. Outcome measures included percentage of total body weight loss as well as comparison with the expected weight loss curve as determined by the Metabolic and Bariatric Surgery Risk/Benefit Calculator. RESULTS: A total of 98 patients were included in the study, with 93 (94.9%) undergoing sleeve gastrectomy and 5 (5.1%) undergoing Roux-en-Y gastric bypass surgery. During the study period, patients were prescribed phentermine and/or topiramate. At postoperative year 1, patients who received pharmacotherapy preoperatively lost 31.3% of their total body weight (TBW) compared with 25.3% TBW for patients with suboptimal weight loss who received medication in the first postoperative year, and 20.8% TBW for patients who did not receive any antiobesity medication in the first postoperative year. Using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) curve for comparison, patients receiving medication preoperatively weighed 2.4% less than expected, whereas patients receiving medication during the first postoperative year weighed 4.8% higher than expected. CONCLUSION: For patients having bariatric surgery who fall below the expected MBSAQIP weight loss curve, early initiation of antiobesity medications can improve the weight loss, with preoperative pharmacotherapy having the greatest effect.