Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

doi:10.1073/pnas.0711978105

Deletion of the mouse RegIIIβ (Reg2) gene disrupts ciliary neurotrophic factor signaling and delays myelination of mouse cranial motor neurons

*National Centre for Cancer Research, Melchor Fernández Almagro, 3. E-28029 Madrid, Spain;
^†Department of Anatomy and Developmental Biology, University College London, Medawar Building, Gower Street, WC1E 6BT London, United Kingdom;
^‡Gene Targeting Laboratory, Institute for Stem Cell Research, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh EH9 3JQ, Scotland;
^§Department of Molecular Biology, Universidad Autonoma de Madrid Cantoblanco, 28049 Madrid, Spain;
^¶Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernandez, Campus de San Juan, Sant Joan d'Alacanti. Nacional 33203550, Alicante, Spain; and
^‖Perinatal Brain Repair Group, Departments of Obstetrics and Gynaecology and Anatomy, University College London, 86-96 Chenies Mews, London WC1E 6HX, United Kingdom

Edited by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, and approved June 16, 2008 (received for review January 2, 2008)

Abstract

A large number of cytokines and growth factors support the development and subsequent maintenance of postnatal motor neurons. RegIIIβ, also known as Reg2 in rat and HIP/PAP1 in humans, is a member of a family of growth factors found in many areas of the body and previously shown to play an important role in both the development and regeneration of subsets of motor neurons. It has been suggested that RegIIIβ expressed by motor neurons is both an obligatory intermediate in the downstream signaling of the leukemia inhibitory factor/ciliary neurotrophic factor (CNTF) family of cytokines, maintaining the integrity of motor neurons during development, as well as a powerful influence on Schwann cell growth during regeneration of the peripheral nerve. Here we report that in mice with a deletion of the RegIIIβ gene, motor neuron survival was unaffected up to 28 weeks after birth. However, there was no CNTF-mediated rescue of neonatal facial motor neurons after axotomy in KO animals when compared with wild-type. In mice, RegIIIβ positive motor neurons are concentrated in cranial motor nuclei that are involved in the patterning of swallowing and suckling. We found that suckling was impaired in RegIIIβ KO mice and correlated this with a significant delay in myelination of the hypoglossal nerve. In summary, we propose that RegIIIβ has an important role to play in the developmental fine-tuning of neonatal motor behaviors mediating the response to peripherally derived cytokines and growth factors and regulating the myelination of motor axons.

Footnotes

**To whom correspondence should be addressed. E-mail: hunt{at}ucl.ac.uk
Author contributions: A.J.H.S., C.D.F., and S.P.H. designed research; L.A.T., S.M.G., C.P.-P., A.S.F., R.B., A.J.H.S., M.T., S.P.-L., A.S., C.D.F., C.R., G.R., and S.P.H. performed research; L.A.T., S.M.G., C.P.-P., A.S.F., A.J.H.S., S.P.-L., and S.P.H. analyzed data; and S.M.G. and S.P.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711978105/DCSupplemental.