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The Journal of Neuroscience, June 7, 2006, 26(23):6364-6376; doi:10.1523/JNEUROSCI.0157-06.2006

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Development/Plasticity/Repair
The Structural and Functional Integrity of Peripheral Nerves Depends on the Glial-Derived Signal Desert Hedgehog

Soheila Sharghi-Namini,¹ Mark Turmaine,¹ Carola Meier,² Vishal Sahni,¹ Fujio Umehara,³ Kristjan R. Jessen,¹ and Rhona Mirsky¹

¹Department of Anatomy and Developmental Biology, University College London, London WC1E 6BT, United Kingdom, ²Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, D-44780 Bochum, Germany, and ³Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan

Correspondence should be addressed to Dr. Rhona Mirsky, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: r.mirsky{at}ucl.ac.uk

We show that desert hedgehog (dhh), a signaling molecule expressed by Schwann cells, is essential for the structural and functional integrity of the peripheral nerve. Dhh-null nerves display multiple abnormalities that affect myelinating and nonmyelinating Schwann cells, axons, and vasculature and immune cells. Myelinated fibers of these mice have a significantly increased (more than two times) number of Schmidt-Lanterman incisures (SLIs), and connexin 29, a molecular component of SLIs, is strongly upregulated. Crossing Dhh-null mice with myelin basic protein (MBP)-deficient shiverer mice, which also have increased SLI numbers, results in further increased SLIs, suggesting that Dhh and MBP control SLIs by different mechanisms. Unmyelinated fibers are also affected, containing many fewer axons per Schwann cell in transverse profiles, whereas the total number of unmyelinated axons is reduced by approximately one-third. In Dhh-null mice, the blood–nerve barrier is permeable and neutrophils and macrophage numbers are elevated, even in uninjured nerves. Dhh-null nerves also lack the largest-diameter myelinated fibers, have elevated numbers of degenerating myelinated axons, and contain regenerating fibers. Transected dhh nerves degenerate faster than wild-type controls. This demonstrates that a single identified glial signal, Dhh, plays a critical role in controlling the integrity of peripheral nervous tissue, in line with its critical role in nerve sheath development (Parmantier et al., 1999). The complexity of the defects raises a number of important questions about the Dhh-dependent cell–cell signaling network in peripheral nerves.

Key words: glia; degeneration; regeneration; hedgehog; PNS; electron microscopy; neuropathy

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Received Jan. 13, 2006; revised April 21, 2006; accepted April 24, 2006.

Correspondence should be addressed to Dr. Rhona Mirsky, Department of Anatomy and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK. Email: r.mirsky{at}ucl.ac.uk

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