Holm Pontus C, Akerud Peter, Wagner Joseph, Arenas Ernest
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
J Neurochem. 2002 Jun;81(6):1318-27. doi: 10.1046/j.1471-4159.2002.00926.x.
Noradrenergic neurons of the locus coeruleus (LC) express the receptor tyrosine kinase c-ret, which binds ligands of the glial cell line-derived neurotrophic factor (GDNF) family. In the present study, we evaluated the function of neurturin (NTN), a GDNF family ligand whose function on LC neurons is unknown. Interestingly, we found that tyrosine hydroxylase (TH)-positive neurons in the LC express both GFRalpha1 and 2 receptors in a developmentally regulated fashion, suggesting a function for their preferred ligands: GDNF and NTN, respectively. Moreover, our results show that NTN mRNA expression is developmentally down-regulated in the LC and peaks in the postnatal hippocampus and cerebral cortex, during the target innervation period. In order to examine the function of NTN, we next performed LC primary cultures, and found that neither GDNF nor NTN promoted the survival of TH-positive neurons. However, both factors efficiently induced neurite outgrowth in noradrenergic neurons (147% and 149% over controls, respectively). Similarly, grafting of fibroblast cell lines engineered to express high levels of NTN did not prevent the loss of LC noradrenergic neurons in a 6-hydroxydopamine (6-OHDA) lesion model, but induced the sprouting of TH-positive cells. Thus our findings show that NTN does not promote the survival of LC noradrenergic neurons, but induces neurite outgrowth in developing noradrenergic neurons in vitro and in a model of neurodegeneration in vivo. These data, combined with data in the literature, suggest that GDNF family ligands are able to independently regulate neuronal survival and/or neuritogenesis.
蓝斑（LC）的去甲肾上腺素能神经元表达受体酪氨酸激酶c-ret，该激酶可结合胶质细胞系源性神经营养因子（GDNF）家族的配体。在本研究中，我们评估了神经营养因子（NTN）的功能，NTN是GDNF家族的一种配体，其对LC神经元的功能尚不清楚。有趣的是，我们发现LC中酪氨酸羟化酶（TH）阳性神经元以发育调控的方式表达GFRalpha1和2受体，这表明它们各自偏好的配体GDNF和NTN具有一定功能。此外，我们的结果表明，NTN mRNA表达在LC中随发育而下调，并在出生后海马体和大脑皮层的靶神经支配期达到峰值。为了研究NTN的功能，我们接下来进行了LC原代培养，发现GDNF和NTN均未促进TH阳性神经元的存活。然而，这两种因子均能有效诱导去甲肾上腺素能神经元的神经突生长（分别比对照组高出147%和149%）。同样，在6-羟基多巴胺（6-OHDA）损伤模型中，移植经基因工程改造以高表达NTN的成纤维细胞系并不能防止LC去甲肾上腺素能神经元的损失，但能诱导TH阳性细胞的芽生。因此，我们的研究结果表明，NTN不能促进LC去甲肾上腺素能神经元的存活，但能在体外和体内神经退行性变模型中诱导发育中的去甲肾上腺素能神经元的神经突生长。这些数据与文献中的数据相结合，表明GDNF家族配体能够独立调节神经元的存活和/或神经突形成。
