Lmx1bIs Required for Maintenance of Central Serotonergic Neurons and Mice Lacking Central Serotonergic System Exhibit Normal Locomotor Activity

• DOI: 10.1523/jneurosci.4143-06.2006
• Publication Date: 2006-12-06T19:08:49Z
• Authors: Zhong-Qiu Zhao; Michael Scott; Santina Chiechio; Jin-Shan Wang; Kenneth J. Renner; Robert W. Gereau; Randy L. Johnson; Evan S. Deneris; Zhou-Feng Chen
• Keywords: Central Nervous System; Homeodomain Proteins; Mice, Knockout; Neurons; 0301 basic medicine; Serotonin; LIM-Homeodomain Proteins; Down-Regulation; Gene Expression Regulation, Developmental; Cell Differentiation; Mice, Transgenic; Motor Activity; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Development ; Differentiation; Lmx1b; Locomotor activity; Serotonergic neurons; Transcription factor; Animals; Transcription Factors

Central serotonergic neurons have been implicated in numerous animal behaviors and psychiatric disorders, but the molecular mechanisms underlying their development are not well understood. Here we generatedLmx1b(LIM homeobox transcription factor 1 β) conditional knock-out mice (Lmx1bf/f/p) in whichLmx1bwas only deleted inPet1(pheochromocytoma 12 ETS factor-1)-expressing 5-HT neurons. InLmx1bf/f/pmice, the initial generation of central 5-HT neurons appeared normal. However, the expression of both 5-HT-specific and non-5-HT-specific markers was lost in these neurons at later stages of development. The loss of gene expression is concomitant with downregulation ofLmx1bexpression, with the exception of serotonin transporterSertand tryptophan hydroxylaseTPH2, whose expression appears to be most sensitive toLmx1b.Interestingly, the expression ofPet1is tightly coupled with expression ofLmx1bduring later stages of embryonic development, indicating thatLmx1bmaintainsPet1expression. InLmx1bf/f/pmice, almost all central 5-HT neurons failed to survive. Surprisingly,Lmx1bf/f/pmice survived to adulthood and exhibited normal locomotor activity. These data reveal a critical role ofLmx1bin maintaining the differentiated status of 5-HT neurons.Lmx1bf/f/pmice with normal locomotor function should provide a unique animal model for examining the roles of central 5-HT in a variety of animal behaviors.