Research report Glial cell line-derived neurotrophic factor receptor GFRa1 is expressed in the rat striatum during postnatal development JinWhan Cho a , Olga Yarygina a , Tinmarla Frances Oo a , Nikolai G. Kholodilov a , Robert E. Burke a,b, * a Department of Neurology, The College of Physicians and Surgeons, Columbia University, Room 308, Black Building, 650 West 168th Street, New York, NY 10032, USA b Department of Pathology, The College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Accepted 12 May 2004 Available online 4 July 2004 Abstract Dopamine neurons of the substantia nigra (SN) undergo a natural cell death event which is biphasic, with peaks at postnatal days (PNDs) 2 and 14. There is growing evidence that GDNF functions as a striatal target-derived neurotrophic factor to regulate the first phase. It has been unknown whether the GDNF receptor, GFRa1, may play a role in regulating either phase. To evaluate a possible role for GFRa1 we have examined its expression throughout postnatal development in the SN and particularly in the striatum, where its expression has been uncertain. GFRa1 mRNA is highly expressed in SN, as previously shown, with highest levels at PND14 – 28. We find that it is also expressed in striatum with a similar time course, but with a more discrete period of maximal expression between PND10 and PND14. The cellular basis of this maximum of expression is an increased number of GFRa1 mRNA-positive medium-sized neurons evenly distributed within the striatum. Immunostaining reveals GFRa1 protein-positive neurons with a similar morphology and distribution. We conclude that GFRa1 is expressed in striatum maximally late in postnatal development. In this location it may act in trans to influence the viability and development of nigral dopamine neurons. D 2004 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Neurotrophic factors: expression and regulation Keywords: GDNF; GFRa1; Natural cell death; Dopamine neurons; Substantia nigra; Striatum 1. Introduction Like most developing neuronal populations, the dopa- mine (DA) neurons of the SN undergo an apoptotic natural cell death (NCD) event [14,13,27]. This event is largely postnatal, and it is biphasic with peaks at PND2 and 14. As envisioned by classic neurotrophic theory [1,8], this event is likely to be regulated by interactions with the target of these neurons, the striatum, because disruption of such interac- tions by target lesion [22], DA neuron terminal lesion [23] or axotomy [9] augments the NCD event. However, the trophic factors mediating this striatal target-derived trophic support have been unknown. One candidate neurotrophic factor for such a role has been GDNF, which was first identified on the basis of its ability to support the development of embryonic mesencephalic DA neurons in culture [20]. In support of this possibility, mRNA for GDNF is highly expressed in the striatum postnatally [3,7,33,34], and mRNA for its receptor, GFRa1, and its signaling kinase, Ret, are highly expressed in SNpc [36,40]. In addition, we have shown that GDNF suppresses apoptotic cell death in DA neurons during the postnatal period both in vitro [5] and in vivo [28], and that intra-striatal injection of neutralizing antibodies to GDNF augments the NCD event in vivo [28]. Neutralization of GDNF within the striatum is able to induce NCD in DA neurons only during the first postnatal week, indicating that it regulates only the first phase [28]. In support of this concept, we have shown that overexpression 0169-328X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.molbrainres.2004.05.015 * Corresponding author. Department of Neurology, The College of Physicians and Surgeons, Columbia University, Room 308, Black Building, 650 West 168th Street, New York, NY 10032, USA. Tel.: +1-212-305- 7374; fax: +1-212-305-5450. E-mail address: rb43@columbia.edu (R.E. Burke). www.elsevier.com/locate/molbrainres Molecular Brain Research 127 (2004) 96 – 104