Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord.
Lhx1 and Lhx5 are co-expressed in multiple interneuron cell types in the developing spinal cord. These include early-born dI4 and dI6 inhibitory interneurons, as well as late-born inhibitory dILA neurons (dILA), all of which express the paired-domain transcription factor Pax2. Although it appears that Lhx1 and Lhx5 do not control the initial specification of the neuronal cell types in which they are expressed, we have found a cell-autonomous requirement for either Lhx1 or Lhx5 to maintain the expression of Pax2, Pax5 and Pax8 in dorsal inhibitory neurons at later developmental stages. Lhx1; Lhx5 double-knockout mice exhibit a downregulation of Gad1 and Viaat (Slc32a1) from E13.5 onwards that is closely associated with a decrease in Pax2 expression. Pax2 is a key factor for dorsal GABAergic identity, with the expression of Pax5 and Pax8 being differentially dependent on Pax2 in the dorsal horn. In summary, our findings support a model in which the differentiation of GABAergic interneurons in the dorsal cord depends on Pax2, with Lhx1 and Lhx5 helping to activate and maintain Pax2 expression in these cells. Lhx1 and Lhx5 therefore function together with Pax2, Pax5 and Pax8 to establish a GABAergic inhibitory-neurotransmitter program in dorsal horn interneurons.
Pillai
Andrea
A
Biology Graduate Program, University of California, San Diego, La Jolla, CA 92037, USA.
Mansouri
Ahmed
A
Behringer
Richard
R
Westphal
Heiner
H
Goulding
Martyn
M
D000818:Animals; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051762:PAX2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018398:Homeodomain Proteins; D007527:Isoenzymes; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; C102995:Lhx5 protein, mouse; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D051762:PAX2 Transcription Factor; D051757:PAX5 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C497319:Pax2 protein, mouse; C497282:Pax5 protein, mouse; C499496:Pax8 protein, mouse; D014157:Transcription Factors; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1