Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord

Author:

Pillai Andrea12,Mansouri Ahmed3,Behringer Richard4,Westphal Heiner5,Goulding Martyn2

Affiliation:

1. Biology Graduate Program, University of California, San Diego, La Jolla, CA 92037, USA.

2. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies,10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

3. Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Gottingen 37077, Germany.

4. Department of Molecular Genetics, University of Texas, M. D. Anderson Cancer Center, Houston, TX 77030, USA.

5. Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.

Abstract

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 dILAneurons (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 Pax2expression. 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 Lhx5helping 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.

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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