Distinct roles for GFR alpha 1 and GFR alpha 2 signalling in different cranial parasympathetic ganglia in vivo

Neurturin (NRTN), signalling via the GDNF family receptor alpha2 (GFR alpha 2) and Ret tyrosine kinase, has recently been identified as an essential ta rget-derived factor for many parasympathetic neurons. NRTN is expressed in salivary and lacrimal glands, while GFR alpha2 and Ret are expressed in the corresponding submandibular, otic and sphenopalatine ganglia. Here, we hav e characterized in more detail the role of GDNF and NRTN signalling in the development of cranial parasympathetic neurons and their target innervation . Gfra1 mRNA was expressed at E12 but not in newborn cranial parasympatheti c ganglia, while Gfra2 mRNA and protein were strongly expressed in newborn and adult cranial parasympathetic neurons and their projections, respective ly. In newborn GFR alpha1- or Ret-deficient mice, where many submandibular ganglion neurons were still present, the otic and sphenopalatine ganglia we re completely missing. In contrast, in newborn GFR alpha2-deficient mice, m ost neurons in all these ganglia were present. In these mice, the loss and atrophy of the submandibular and otic neurons were amplified postnatally, a ccompanied by complete loss of innervation in some target regions and prese rvation in others. Surprisingly, GFR alpha2-deficient sphenopalatine neuron s, whose targets were completely uninnervated, were not reduced in number a nd only slightly atrophied. Thus, GDNF signalling via GFR alpha1/Ret is ess ential in the early gangliogenesis of some, but not all, cranial parasympat hetic neurons, whereas NRTN signalling through GFR alpha2/Ret is essential for the development and maintenance of parasympathetic target innervation. These results indicate that GDNF and NRTN have distinct functions in develo ping parasympathetic neurons, and suggest heterogeneity among and within di fferent parasympathetic ganglia.