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Volume 17, Number 3, Issue of February 1, 1997 pp. 1168-1178
Copyright ©1997 Society for Neuroscience

Morphological Alterations in the Peripheral and Central Nervous Systems of Mice Lacking Glial Cell Line-Derived Neurotrophic Factor (GDNF): Immunohistochemical Studies

Received Aug. 29, 1996; revised Nov. 18, 1996; accepted Nov. 22, 1996.

Ann-Charlotte E. Granholm^{1, 2, 3}, Nisha Srivastava¹, Justin L. Mott¹, Stephanie Henry¹, Michael Henry¹, Heiner Westphal⁴, Jose G. Pichel⁴, Liya Shen⁴, and Barry J. Hoffer^{2, 3}

Departments of ¹ Basic Science and ² Pharmacology and ³ Neuroscience Training Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, and ⁴ National Institute of Child Health and Human Development, LMGD, National Institutes of Health, Bethesda, Maryland 20892

Glial cell line-derived neurotrophic factor (GDNF) is a member of the TGF- superfamily of growth factors with neurotrophic activity on midbrain dopaminergic neurons and on developing and mature motoneurons of the brainstem and spinal cord. To investigate the extent of GDNF dependency of central and peripheral nervous structures during development, we have performed an immunohistochemical analysis of sections from the whole head including brain, peripheral ganglia, developing teeth and tongue, as well as intestines, in mutant mice lacking a part of the third exon that encodes the GDNF protein. As described previously, these null-mutated mice lack most of the enteric nerve plexus and are subject to agenesis or severe dysgenesis of the kidneys. In the present communication, we examined the development of vibrissae and incisor and molar teeth, as well as the innervation of these structures, and found no differences between null-mutated and control mice. A decrease in the immunohistochemical labeling intensity with tyrosine hydroxylase was observed in the superior cervical ganglion (SCG), as well as in the pontine nucleus locus coeruleus, and the sympathetic innervation of blood vessels and glands in the head was significantly decreased. None of the brain nuclei studied exhibited any significant decreases in the total number of neurons, but the packing density of neurons in the nucleus locus coeruleus was decreased. These data indicate that GDNF might be one neurotrophic factor that contributes to the development of central and peripheral noradrenergic neurons.

Key words: glial cell line-derived neurotrophic factor; aminergic neurons; substantia nigra; locus coeruleus; gastrointestinal innervation; tooth development; basal forebrain

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