Cellular expression of GDNF mRNA suggests multiple functions inside and outside the nervous system

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) is a distant member of the transforming growth factor-beta family and has potent neurotrophic effects on several classes of neurons including dopamine neurons and motoneurons. Here, we have used in situ hybridization to describe the development of the cellular expression of GDNF mRNA pre- and postnatally. Consistent with dopaminotrophic activity, GDNF mRNA is expressed in the developing basal ganglia and the olfactory tubercle. It is also found in a thalamic nucleus, in neurons of the substantia innominata, in the developing Purkinje neurons and the developing locus coeruleus area, and in trigeminal brainstem nuclei. In the spinal cord, neuronal expression is found in Clarke's column. GDNF mRNA is also expressed in the dorsal horns during development. Additional GDNF mRNA expression in the head region includes the carotid body, the retina, the vibrissae, the inner ear, the ear canal, and epithelium in the nasal cavity. Prominent expression is also found in the developing teeth. The widespread expression of GDNF in developing skeletal muscle is consistent with trophic activity on alpha-motoneurons. The smooth muscle layers of the gastrointestinal tract are also strongly positive. A very strong signal is found in the outer mesenchyme of the developing metanephric kidney. We conclude that GDNF mRNA is expressed in many different cellular systems inside and outside the central nervous system during development, suggesting multiple functions of GDNF in the developing organism.

Neurturin and Glial Cell Line-Derived Neurotrophic Factor Receptor-β (GDNFR-β), Novel Proteins Related to GDNF and GDNFR-α with Specific Cellular Patterns of Expression Suggesting Roles in the Developing and Adult Nervous System and in Peripheral Organs

“…The discovery of neurturin, a protein with neurotrophic properties (Kotzbauer et al, 1996) and 42% amino acid homology to GDNF (Lin et al, 1993;Unsicker, 1996) prompted this first in situ hybridization study of NTN mRNA expression patterns to complement the patterns of expression of GDNF as described by us and others (Strömberg et al, 1993;Hellmich et al, 1996;Nosrat et al, 1996;Suvanto et al, 1996).…”

“…A 50 mer random control probe was used as Table 1. Data were compiled from the present study and Nosrat et al (1996and Nosrat et al ( , 1997.…”

“…The in situ hybridization protocol using radiolabeled oligonucleotides was according to the method of Dagerlind et al (1992) (also see Nosrat et al, 1996). After development, the slides were counterstained with cresyl violet or toluidine blue and mounted (Entellan; Merck, Darmstadt, Germany).…”

“…Pairs of probes generated the same hybridization patterns. The GDN F, RET, and GDN FR-␣ probes have been characterized previously (Nosrat et al, 1996(Nosrat et al, , 1997. All hybridization was performed under high stringency conditions.…”

“…Glial cell line-derived neurotrophic factor (GDN F) (Lin et al, 1993;Unsicker, 1996;Olson, 1997) is a distant member of the TGF-␤ superfamily, which is expressed in many neuronal and non-neuronal tissues during development and, to a lesser extent, in the adult animal (Schaar et al, 1993;Strömberg et al, 1993;Henderson et al, 1994;Hellmich et al, 1996;Nosrat et al, 1996;Suvanto et al, 1996). GDN F signaling is mediated through a two-component system consisting of a glycosyl-phosphatidylinositol-linked protein termed GDN F receptor-␣ (GDNFR-␣) (Jing et al, 1996;Treanor et al, 1996), which binds GDNF, after which the GDN F-GDN FR-␣ complex binds to and activates the tyrosine kinase receptor RET (Durbec et al, 1996;Trupp et al, 1996).…”