Wnt1-regulated genetic networks in midbrain dopaminergic neuron development.
Wurst W1, Prakash N.Author information 1Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, and Technische Universität München-Weihenstephan, Lehrstuhl für Entwicklungsgenetik, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.AbstractNeurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain (VM), and controls and modulates the execution of motor, cognitive, affective, motivational, and rewarding behaviours. Degeneration of these neurons leads to motor deficits that are characteristic of Parkinson's disease, while their dysfunction is involved in the pathogenesis of psychiatric disorders including schizophrenia and addiction. Because the aetiology and therapeutic prospects for these diseases include neurodevelopmental aspects, substantial scientific interest has been focused on deciphering the mechanistic pathways that control the generation and survival of these neurons during embryonic development. Researches during the last decade revealed the pivotal role of the secreted Wnt1 ligand and its signalling cascade in the generation of the dopamine-synthesizing neurons in the mammalian VM. Here, we summarize the initial and more recent findings that have unravelled several Wnt1-controlled genetic networks required for the proliferation and commitment of VM progenitors to the dopaminergic cell fate during midgestational embryonic stages, and for the correct differentiation of these progenitors into postmitotic dopamine-synthesizing neurons at late midgestational embryonic and foetal stages.
Journal of molecular cell biology.J Mol Cell Biol.2014 Feb;6(1):34-41. doi: 10.1093/jmcb/mjt046. Epub 2013 Dec 9.
Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain (VM), and controls and modulates the execution of motor, cognitive, affective, mo
Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway.
Tortoriello G1, Morris CV, Alpar A, Fuzik J, Shirran SL, Calvigioni D, Keimpema E, Botting CH, Reinecke K, Herdegen T, Courtney M, Hurd YL, Harkany T.Author information 1Division of Molecular Neurobiology Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.AbstractChildren exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring.
The EMBO journal.EMBO J.2014 Jan 27. [Epub ahead of print]
Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid
Interleukin-10 regulates the fetal hyaluronan-rich extracellular matrix via a STAT3-dependent mechanism.
King A1, Balaji S, Marsh E, Le LD, Shaaban AF, Crombleholme TM, Keswani SG.Author information 1The Center for Molecular Fetal Therapy, Division of Pediatric, Thoracic and General Surgery, Cincinnati Children's Hospital and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.AbstractBACKGROUND: The midgestational fetus is capable of regenerative healing. We have recently demonstrated a novel role for the anti-inflammatory cytokine interleukin 10 (IL-10) as a regulator of hyaluronan (HA) in the extracellular matrix. The signaling pathway of IL-10 has been studied in monocytes but is unknown in dermal fibroblasts. We hypothesized IL-10 signals through its primary receptor, IL-10R1, to activate STAT3, resulting in HA synthesis.
The Journal of surgical research.J Surg Res.2013 Sep;184(1):671-7. doi: 10.1016/j.jss.2013.04.009. Epub 2013 Apr 24.
BACKGROUND: The midgestational fetus is capable of regenerative healing. We have recently demonstrated a novel role for the anti-inflammatory cytokine interleukin 10 (IL-10) as a regulator of hyaluronan (HA) in the extracellular matrix. The signaling pathway of IL-10 has been studied in monocytes bu
The potential for producing reproductive toxicity or teratogenesis in mice by exposure to magnetic resonance imaging (MRI) conditions was evaluated by means of.
J Pediatr Surg. 2007 Jun;42(6):966-71; discussion 971-3. Rapid closure of midgestational excisional wounds in a fetal mouse model is associated with altered transforming growth factor-beta isoform and receptor expression. Goldberg SR ...