Disabled‐1 dorsal horn spinal cord neurons co‐express Lmx1b and function in nociceptive circuits

The Reelin‐signaling pathway is essential for correct neuronal positioning within the central nervous system. Mutant mice with a deletion of Reelin, its lipoprotein receptors, or its intracellular adaptor protein Disabled‐1 (Dab1), exhibit nociceptive abnormalities: thermal (heat) hyperalgesia and r...

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Bibliographic Details
Published in:	The European journal of neuroscience 2017-03, Vol.45 (5), p.733-747
Main Authors:	Yvone, Griselda M., Zhao‐Fleming, Hannah H., Udeochu, Joe C., Chavez‐Martinez, Carmine L., Wang, Austin, Hirose‐Ikeda, Megumi, Phelps, Patricia E., Barrot, Michel
Format:	Article
Language:	eng
Subjects:	Abnormalities Animals Cell Adhesion Molecules, Neuronal - genetics Cell Adhesion Molecules, Neuronal - metabolism Central nervous system Circuits Disabled-1 protein Dorsal horn Extracellular Matrix Proteins - genetics Extracellular Matrix Proteins - metabolism Glutamatergic transmission Homeobox Immunofluorescence Interneurons lateral cervical nucleus lateral spinal nucleus LIM-Homeodomain Proteins - genetics LIM-Homeodomain Proteins - metabolism Lipoprotein receptors Mechanical stimuli Mice Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nervous system neuronal migration disorders Neurons Nociception Nuclei pain Pain perception Posterior Horn Cells - metabolism Posterior Horn Cells - physiology Reeler mouse Reelin protein Rodents Serine Endopeptidases - genetics Serine Endopeptidases - metabolism Signal transduction Spinal cord Stimulation Transcription Factors - genetics Transcription Factors - metabolism
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Summary:	The Reelin‐signaling pathway is essential for correct neuronal positioning within the central nervous system. Mutant mice with a deletion of Reelin, its lipoprotein receptors, or its intracellular adaptor protein Disabled‐1 (Dab1), exhibit nociceptive abnormalities: thermal (heat) hyperalgesia and reduced mechanical sensitivity. To determine dorsal horn alterations associated with these nociceptive abnormalities, we first characterized the correctly positioned Dab1 neurons in wild‐type and mispositioned neurons in Reelin‐signaling pathway mutant lumbar spinal cord. Using immunofluorescence, we found that 70% of the numerous Dab1 neurons in Reln+/+ laminae I–II and 67% of those in the lateral reticulated area and lateral spinal nucleus (LSN) co‐express the LIM‐homeobox transcription factor 1 beta (Lmx1b), an excitatory glutamatergic neuron marker. Evidence of Dab1‐ and Dab1‐Lmx1b neuronal positioning errors was found within the isolectin B4 terminal region of Reln−/− lamina IIinner and in the lateral reticulated area and LSN, where about 50% of the Dab1‐Lmx1b neurons are missing. Importantly, Dab1‐Lmx1b neurons in laminae I–II and the lateral reticulated area express Fos after noxious thermal or mechanical stimulation and thus participate in these circuits. In another pain relevant locus – the lateral cervical nucleus (LCN), we also found about a 50% loss of Dab1‐Lmx1b neurons in Reln−/− mice. We suggest that extensively mispositioned Dab1 projection neurons in the lateral reticulated area, LSN, and LCN and the more subtle positioning errors of Dab1 interneurons in laminae I–II contribute to the abnormalities in pain responses found in Reelin‐signaling pathway mutants. Reelin‐signaling pathway mutant mice are hypersensitive to thermal and insensitive to mechanical stimulation yet the anatomical abnormalities that cause these alterations are unclear. Here we show that 70% of Disabled‐1‐expressing dorsal horn neurons in laminae I–II (see image) and lateral lamina V co‐express the transcription factor Lmx1b, a marker of glutamatergic neurons. We also found that these Disabled‐1‐Lmx1b neurons are incorrectly positioned in nociceptive areas of mutant dorsal horns.
ISSN:	0953-816X 1460-9568