TGF-β Signaling Regulates Development of Midbrain Dopaminergic and Hindbrain Serotonergic Neuron Subgroups. 2018

Enaam Chleilat, and Lena Skatulla, and Belal Rahhal, and Manal T Hussein, and Melanie Feuerstein, and Kerstin Krieglstein, and Eleni Roussa
Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: enaam.chleilat@anat.uni-freiburg.de.

Molecular and functional diversity within midbrain dopaminergic (mDA) and hindbrain serotonergic (5-HT) neurons has emerged as a relevant feature that could underlie selective vulnerability of neurons in clinical disorders. We have investigated the role of transforming growth factor beta (TGF-β) during development of mDA and 5-HT subgroups. We have generated TβRIIflox/flox::En1cre/+ mice where type II TGF-β receptor is conditionally deleted from engrailed 1-expressing cells and have investigated the hindbrain serotonergic system of these mice together with Tgf-β2-/- mice. The results show a significant decrease in the number of 5-HT neurons in TGF-β2-deficient mice at embryonic day (E) 12 and a selective significant decrease in the hindbrain paramedian raphe 5-HT neurons at E18, compared to wild type. Moreover, conditional deletion of TGF-β signaling from midbrain and rhombomere 1 leads to inactive TGF-β signaling in cre-expressing cells, impaired development of mouse mDA neuron subgroups and of dorsal raphe 5-HT neuron subgroups in a temporal manner. These results highlight a selective growth factor dependency of individual rostral hindbrain serotonergic subpopulations, emphasize the impact of TGF-β signaling during development of mDA and 5-HT subgroups, and suggest TGF-βs as potent candidates to establish diversity within the hindbrain serotonergic system. Thus, the data contribute to a better understanding of development and degeneration of mDA neurons and 5-HT-associated clinical disorders.

UI MeSH Term Description Entries
D008636 Mesencephalon The middle of the three primitive cerebral vesicles of the embryonic brain. Without further subdivision, midbrain develops into a short, constricted portion connecting the PONS and the DIENCEPHALON. Midbrain contains two major parts, the dorsal TECTUM MESENCEPHALI and the ventral TEGMENTUM MESENCEPHALI, housing components of auditory, visual, and other sensorimoter systems. Midbrain,Mesencephalons,Midbrains
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D004622 Embryo, Mammalian The entity of a developing mammal (MAMMALS), generally from the cleavage of a ZYGOTE to the end of embryonic differentiation of basic structures. For the human embryo, this represents the first two months of intrauterine development preceding the stages of the FETUS. Embryonic Structures, Mammalian,Mammalian Embryo,Mammalian Embryo Structures,Mammalian Embryonic Structures,Embryo Structure, Mammalian,Embryo Structures, Mammalian,Embryonic Structure, Mammalian,Embryos, Mammalian,Mammalian Embryo Structure,Mammalian Embryonic Structure,Mammalian Embryos,Structure, Mammalian Embryo,Structure, Mammalian Embryonic,Structures, Mammalian Embryo,Structures, Mammalian Embryonic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012249 Rhombencephalon The posterior of the three primitive cerebral vesicles of an embryonic brain. It consists of myelencephalon, metencephalon, and isthmus rhombencephali from which develop the major BRAIN STEM components, such as MEDULLA OBLONGATA from the myelencephalon, CEREBELLUM and PONS from the metencephalon, with the expanded cavity forming the FOURTH VENTRICLE. Hindbrain,Hind Brain,Brain, Hind,Brains, Hind,Hind Brains,Hindbrains,Rhombencephalons
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D016212 Transforming Growth Factor beta A factor synthesized in a wide variety of tissues. It acts synergistically with TGF-alpha in inducing phenotypic transformation and can also act as a negative autocrine growth factor. TGF-beta has a potential role in embryonal development, cellular differentiation, hormone secretion, and immune function. TGF-beta is found mostly as homodimer forms of separate gene products TGF-beta1, TGF-beta2 or TGF-beta3. Heterodimers composed of TGF-beta1 and 2 (TGF-beta1.2) or of TGF-beta2 and 3 (TGF-beta2.3) have been isolated. The TGF-beta proteins are synthesized as precursor proteins. Bone-Derived Transforming Growth Factor,Platelet Transforming Growth Factor,TGF-beta,Milk Growth Factor,TGFbeta,Bone Derived Transforming Growth Factor,Factor, Milk Growth,Growth Factor, Milk
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055495 Neurogenesis Formation of NEURONS which involves the differentiation and division of STEM CELLS in which one or both of the daughter cells become neurons. Neurogeneses
D059290 Dopaminergic Neurons Neurons whose primary neurotransmitter is DOPAMINE. Dopamine Neurons,Dopamine Neuron,Dopaminergic Neuron,Neuron, Dopamine,Neuron, Dopaminergic,Neurons, Dopamine,Neurons, Dopaminergic

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