A transcriptional network coordinately determines transmitter and peptidergic fate in the dorsal spinal cord

Abstract

Dorsal horn neurons express many different neuropeptides that modulate sensory perception like the sensation of pain. Inhibitory neurons of the dorsal horn derive from postmitotic neurons that express Pax2, Lbx1 and Lhx1/5, and diversify during maturation. In particular, fractions of maturing inhibitory neurons express various neuropeptides. We demonstrate here that a coordinate molecular mechanism determines inhibitory and peptidergic fate in the developing dorsal horn. A bHLH factor complex that contains Ptf1a acts as upstream regulator and initiates the expression of several downstream transcription factors in the future inhibitory neurons, of which Pax2 is known to determine the neurotransmitter phenotype. We demonstrate here that dynorphin, galanin, NPY, nociceptin and enkephalin expression depends on Ptf1a, indicating that these neuropeptides are expressed in inhibitory neurons. Furthermore, we show that Neurod1/2/6 and Lhx1/5, which act downstream of Ptf1a, control distinct aspects of peptidergic differentiation. In particular, the Neurod1/2/6 factors are essential for dynorphin and galanin expression, whereas the Lhx1/5 factors are essential for NPY expression. We conclude that a transcriptional network operates in maturing dorsal horn neurons that coordinately determines transmitter and peptidergic fate.

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

“…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).…”

“…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.…”

“…Previous studies have characterized the pattern of peptide expression in GABAergic neurons, including neuropeptide Y (NPY), nociceptin/orphanin FQ (N/ OFQ), an early wave of somatostatin (SOM), enkephalin (ENK), dynorphin (DYN), and galanin (GAL) (Bröhl et al, 2008;Huang et al, 2008;Xu et al, 2008). For glutamatergic neurons, transcription factors Gsx1/2, which lie upstream of Tlx3, are known to control the expression of those genes encoding cholecystokinin (CCK), substance P (SP), gastrin-releasing peptide (GRP), and PACAP/Adcyap1 in the dorsal spinal cord (Mizuguchi et al, 2006;Bröhl et al, 2008). Both Tlx1 and Tlx3 are required for the specification of glutamatergic cell fate and the expression of peptide genes encoding CCK, SP, and GRP in dorsal horn (Cheng et al, 2004;Li et al, 2006;Xu et al, 2008).…”

“…Therefore, transcription factors Tlx1/3 are required for the coordination of cell fate and the peptide gene expression in glutamatergic neurons in the dorsal spinal cord (Cheng et al, 2004;Li et al, 2006;Xu et al, 2008). This is reminiscent of the fact that transcription factor Ptf1a coordinates the cell fate and peptide gene expression in GABAergic neurons in the dorsal spinal cord (Glasgow et al, 2005;Mizuguchi et al, 2006;Bröhl et al, 2008;Huang et al, 2008 …”

Un circuit impliqué dans les démangeaisons mécaniques identifié au niveau de la moelle épinière

“…Néanmoins, plusieurs populations ont pu être identifiées chez l'adulte sur la base de l'expression de neuropeptides et de diverses protéines. Ainsi certains neuropeptides (comme la somatostatine, la substance P ou la neurotensine) ou des protéines fixant le calcium (la calbindine et la calrétinine) ont été identifiés dans des sous-types d'interneurones excitateurs alors que d'autres (le neuropeptide Y [NPY], la galanine, la parvalbumine) sont majoritairement exprimés dans des sous-types de neurones inhibiteurs [3,4] (Figure 1B Figure 1C) qui permet de manipuler génétique-ment la plupart de ces interneurones. Il est en effet maintenant possible 3 L'intersection de l'expression de différents gènes dans une même population cellulaire permet, grâce à l'utilisation de souris géné-tiquement modifiées exprimant différentes recombinases sous le contrôle de ces gènes, de les cibler spécifiquement.…”