Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency

Ning-Ning Song,Jian-Bo Xiu,Klaus Peter Lesch,Lei Zhang,He Li,Ying Huang,Lise Gutknecht,Yu-Qiang Ding,Jia-Yin Chen,Etienne Joly

doi:10.1371/journal.pone.0015998

Abstract

The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreERT2 mice were generated and crossed with Lmx1bflox/flox mice to obtain Pet1-CreERT2; Lmx1bflox/flox mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2.

Highlights

The neurotransmitter serotonin (5-HT) exerts a wide spectrum of actions in a variety of behaviors, such as pain sensation, locomotion, circadian rhythm, food intake and emotional behaviors [1,2]
Sonic hedgehog secreted from the floor plate triggers the expression of Mash1 and GATA2 in progenitor cells in the ventricular zone of hindbrain [6], and both genes are essential for the development of 5HTergic neurons [7,8]. 5-HTergic neurons are classified into two groups based on their anatomical location: a rostral group located in the pons and a caudal group located in the medulla oblongata
Nkx2.2 is expressed in the progenitors of all 5-HTergic neurons in hindbrain, evidence from null mutant mice show that it is only required for the generation of 5-HTergic neurons in the dorsal raphe nucleus, one cluster neurons in pons group [9], and GATA3 is thought to be required for the differentiation of the medulla oblongata group [10]

Summary

Introduction

The neurotransmitter serotonin (5-HT) exerts a wide spectrum of actions in a variety of behaviors, such as pain sensation, locomotion, circadian rhythm, food intake and emotional behaviors [1,2]. Nkx2.2 is expressed in the progenitors of all 5-HTergic neurons in hindbrain, evidence from null mutant mice show that it is only required for the generation of 5-HTergic neurons in the dorsal raphe nucleus, one cluster neurons in pons group [9], and GATA3 is thought to be required for the differentiation of the medulla oblongata group [10]. Both Lmx1b and Pet are expressed in postmitotic 5HTergic neurons and essential for the differentiation and survival of 5HTergic neurons during embryonic development [4,11,12]. Lmx1b, an essential gene for the development of central 5HTergic neurons, is required for the normal biosynthesis of 5HT in the adult brain and possibly for regulating normal functions of central 5-HTergic neurons

Methods

Results

Conclusion