Tlx1 and Tlx3 Coordinate Specification of Dorsal Horn Pain-Modulatory Peptidergic Neurons

Abstract

The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3 ϩ spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons.

Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord

“…Furthermore, whether other transmitter receptor genes in general are controlled by Tlx1/3 or Ptf1a is unknown. Previous studies have also characterized the transcriptional regulation of peptides in glutamatergic and GABAergic neurons (Bröhl et al, 2008;Huang et al, 2008;Xu et al, 2008). In this study, we have further shown that two genes encoding additional peptides, adenylate cyclase activating polypeptide 1 (PACAP/Adcyap1) and neurotensin (NT), are controlled by Tlx1/3.…”

“…Another transcription factor Ptf1a acts to suppress Tlx3 expression and promote GABAergic differentiation (Glasgow et al, 2005;Mizuguchi et al, 2006;Hori et al, 2008). Three studies including ours have also shown that the transcription factors that determine the glutamatergic or GABAergic cell fate also control the expression of distinct sets of peptides in the dorsal horn selectively (Bröhl et al, 2008;Huang et al, 2008;Xu et al, 2008).…”

c-Maf Is Required for the Development of Dorsal Horn Laminae III/IV Neurons and Mechanoreceptive DRG Axon Projections

“…؊/؊ embryos We have demonstrated previously that transcription factors Tlx1 and Tlx3 specify the glutamatergic cell fate and control a set of downstream targets including transcription factors, peptides, and transmitter receptors in the dorsal horn (Qian et al, 2002;Cheng et al, 2004;Cheng et al, 2005;Xu et al, 2008) (data not shown). The specific expression patterns of MafA and c-Maf prompted us to investigate whether MafA and c-Maf were involved in a transcriptional cascade to control the expression of some target genes of Tlx1 and Tlx3 in the developing dorsal spinal cord.…”

“…The generation of Tlx1, Tlx3, Lbx1, and Tlx3-cre mutant mice has been described previously (Roberts et al, 1994;Gross et al, 2000;Shirasawa et al, 2000;Xu et al, 2008). Ptf1a cre mutant mice, which have Cre-recombinase in place of the Ptf1a protein-coding region, were kindly donated by Dr. Christopher Wright (Vanderbilt University, Nashville, TN) and obtained from the Mutant Mouse Regional Resource Centers (MMRRC) (Kawaguchi et al, 2002).…”

Vesicle capture, not delivery, scales up neuropeptide storage in neuroendocrine terminals

“…For example, cAMP response element binding protein (CREB) was originally described as a cAMP-dependent transcriptional stimulator for somatostatin (2). Furthermore, transcriptional networks specify peptidergic neurons in Drosophila and mammals (e.g., [3][4][5][6][7][8][9]. Finally, accumulation of amidated neuropeptides and DCVs in Drosophila neurons is enhanced by the transcription factor Dimmed (DIMM) (10)(11)(12)(13).…”