Lmx1b is essential for the development of serotonergic neurons

Ding, Yu; Marklund, Ulrika; Yuan, Wenlin; Yin, Jun; Wegman, Lauren J.; Ericson, Johan; Deneris, Evan S.; Johnson, Randy L.; Chen, Zhou Feng

doi:10.1038/nn1104

Cited by 238 publications

(253 citation statements)

References 26 publications

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“…In situ hybridization was performed as previously described (19). For the mouse MOR probe, the MOR plasmid was cut with HindIII and transcribed with SP6 RNA polymerase to produce the antisense cRNA probe (53).…”

Section: Methodsmentioning

confidence: 99%

“…We have generated a line of conditional knockout mice called Lmx1b f/f/p mice in which the transcription factor Lmx1b, which is essential for the development of 5-HT neurons in the hindbrain, is selectively deleted in cells expressing Pet1 (19)(20)(21). Because 5-HT neurons lacking Lmx1b fail to survive, the deletion of Lmx1b results in the specific loss of the central 5-HT neurons in Lmx1b f/f/p mice (21).…”

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confidence: 99%

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Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1b f/f/p ), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a opioid receptor agonist administered at the supraspinal level was abolished in Lmx1b f/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1b f/f/p mice exhibited significantly reduced analgesic effects of and ␦ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1b f/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system. serotonin ͉ pain ͉ conditioned place preference ͉ behavior ͉ mouse

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…While genetic inactivation of the upstream transcription factors Lmx1b and Pet1 compromises the development of the majority of 5-HT neurons [16, 17,51], it is concluded that intrinsic 5-HT production is neither essential for the development maintenance and survival of serotonergic neurons, nor for the molecular specification of a serotonergic-like phenotype. This further suggests that the developmental role of 5-HT in the maturation/differentiation of the 5-HT system itself has been overvalued, and the notion of an autoregulation of 5-HT system development [6,7] may need to be addressed from a new standpoint.…”

Section: Tph2 In Personality Traits Of Negative Emotionality and In Dmentioning

confidence: 99%

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

Lesch

Araragi

Waider

et al. 2012

Phil. Trans. R. Soc. B

129

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Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111 -140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581 -604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.Keywords: tryptophan hydroxylase (TPH2); cognition; emotion; impulsivity; aggression; violence INTRODUCTIONNegative emotionality, aggression and antisociality are complex temperamental traits and social behaviours that arise out of multiple causes involving biological and psychological dynamisms and social forces, and different forms of emotional behaviour may each result from different biopsychosocial pathways. The societal implications of aggressiveness, which results in numerous facets of aggressive behaviour and ranges from the establishment of hierarchies and dominance to antisocial behaviour and delinquency, have been examined with preclinical and clinical frameworks.Developmentally inappropriate conduct, aggressiveness and failure in social adjustment represent the most detrimental and harmful long-term outcome of a wide spectrum of neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation.In both humans and animals, the term aggression comprises a variety of behaviours that are heterogeneous for clinical phenomenology and neurobiological features. While the impact of complex cultural variables on behaviour impedes simple extrapolation of animal phenotypes to human traits, clinical observation, experimental paradigms in the laboratory and cluster/ factor-analytic statistics have been used in attempts to subdivide aggression. On the basis of different approaches, hu...

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“…Additionally, 5HT neurotransmission is modulated through abundant afferent information arising from, for example, other monoaminergic systems (8,9) and from orexinergic, glutamatergic, and GABAergic pathways (10)(11)(12). The remarkably expansive neuromodulatory influence of 5HT is the product of a complex transcriptional cascade that generates 5HT-synthesizing neurons in the ventral hindbrain (13)(14)(15)(16)(17)(18). 5HT also figures prominently in mental health disorders as a number of lines of evidence provide strong support for the hypothesis that altered serotonergic signaling contributes to neurological and psychiatric pathogenesis (19)(20)(21)(22).…”

mentioning

confidence: 99%

“…Recent gene-targeting studies of 5HT neurons are also limited in that most of the targeted genes reported to date are ubiquitously expressed and play essential roles in early development. Consequently, propagation of their homozygous null alleles in the mouse results in embryonic or early postnatal death (13,17). Thus, an approach to conveniently alter gene expression in a 5HT neuron-specific manner would greatly facilitate studies of the 5HT transmitter system.…”

mentioning

confidence: 99%

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

Scott

Wylie

Lerch

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

210

241

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Serotonin (5HT) is a critical modulator of neural circuits that support diverse behaviors and physiological processes, and multiple lines of evidence implicate abnormal serotonergic signaling in psychiatric pathogenesis. The significance of 5HT underscores the importance of elucidating the molecular pathways involved in serotonergic system development, function, and plasticity. However, these mechanisms remain poorly defined, owing largely to the difficulty of accessing 5HT neurons for experimental manipulation. To address this methodological deficiency, we present a transgenic route to selectively alter 5HT neuron gene expression. This approach is based on the ability of a Pet-1 enhancer region to direct reliable 5HT neuron-specific transgene expression in the CNS. Its versatility is illustrated with several transgenic mouse lines, each of which provides a tool for 5HT neuron studies. Two lines allow Cre-mediated recombination at different stages of 5HT neuron development. A third line in which 5HT neurons are marked with yellow fluorescent protein will have numerous applications, including their electrophysiological characterization. To demonstrate this application, we have characterized active and passive membrane properties of midbrain reticular 5HT neurons, which heretofore have not been reported to our knowledge. A fourth line in which Pet-1 loss of function is rescued by expression of a Pet-1 transgene demonstrates biologically relevant levels of transgene expression and offers a route for investigating serotonergic protein structure and function in a behaving animal. These findings establish a straightforward and reliable approach for developing an array of tools for in vivo and in vitro studies of 5HT neurons.Cre recombinase ͉ pet-1 ͉ transgenic ͉ yellow fluorescent protein ͉ monoamine S erotonin (5HT) is a transmitter of broad relevance to nervous system development and function (1-4). Serotonergic pathways innervate most cytoarchitectonic structures of the CNS, and accordingly they have been implicated in the modulation of circuitry involved in nearly all behaviors and physiological processes (3, 5-7). Additionally, 5HT neurotransmission is modulated through abundant afferent information arising from, for example, other monoaminergic systems (8, 9) and from orexinergic, glutamatergic, and GABAergic pathways (10-12). The remarkably expansive neuromodulatory influence of 5HT is the product of a complex transcriptional cascade that generates 5HT-synthesizing neurons in the ventral hindbrain (13-18). 5HT also figures prominently in mental health disorders as a number of lines of evidence provide strong support for the hypothesis that altered serotonergic signaling contributes to neurological and psychiatric pathogenesis (19)(20)(21)(22). Despite considerable progress in understanding the importance of 5HT neurotransmission, however, the mechanisms governing 5HT neuron development and the precise physiological roles of 5HT in the modulation of CNS circuitry are not yet clear.Studies of 5HT neurons are hind...

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Lmx1b is essential for the development of serotonergic neurons

Cited by 238 publications

References 26 publications

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

A genetic approach to access serotonin neurons forin vivoandin vitrostudies

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