Second, SADs might be required for retrograde signaling Autophagy Compound Library cost by NT-3. Third, SADs might mediate effects of NT-3 on axonal arborization. We tested these alternatives in turn. We examined peripheral projections of sensory neurons innervating muscle (proprioceptors), Merkel cells, and whisker follicles. Parvalbumin-positive proprioceptive axons grew into forelimb and hindlimb muscles of SADIsl1-cre mutants in a manner indistinguishable

from controls; within muscles, the IaPSN axons formed characteristic vesicle-rich (synaptotagmin-positive) annulospiral endings on intrafusal muscle fibers of forelimb and hindlimb muscles ( Figures 3K, 3M, and S3K–S3L″). Golgi tendon organs were also innervated normally in SADIsl1-cre animals ( Figures 3L and 3N). Similarly, in both control and SADIsl1-cre mutants, trunk sensory axons formed normal disc shaped endings on Merkel cells in the epidermis ( Figures 3O and 3Q) and axons in the deep vibrissal nerve innervated whisker follicles ( Figures 3P and 3R). In addition, PV+ DRG neurons acquired a pseudounipolar morphology by E15.5 ( Figures S3M and S3N), a cellular feature that occurs upon peripheral innervation ( Matsuda and Uehara, 1984). Thus, defects in central projections of SAD-deficient sensory neurons do not result from

failure of peripheral processes to reach sources of neurotrophic factors. We then asked whether SADs are required in IaPSNs for retrograde signaling by NT-3 through its whatever receptor, TrkC. Expression of Selleck RAD001 TrkC was not affected by the loss of SAD kinases (Figures S4A and S4B″). When

apoptosis is blocked in the absence of NT-3/TrkC signaling, the size of parvalbumin-positive neurons and levels of the transcription factor ER81 are reduced (Patel et al., 2003). None of these defects were observed in SADIsl1-cre mice ( Figures 4A and 4E and Figures S4C–S4H) indicating that SAD kinases are not required for retrograde NT-3 signaling or for the acquisition of morphological or molecular characteristics induced by NT-3. To ask whether SADs mediate effects of NT-3 on IaPSNs, we cultured DRG explants from control and SADIsl1-cre animals in the presence of NT-3 and measured axon outgrowth. Under these conditions, only NT-3 dependent neurons survive ( Hory-Lee et al., 1993). Outgrowth of axons from these neurons was decreased by nearly half in SADIsl1-cre mutant ganglia relative to controls ( Figures 4F, 4G, and 4J). We also cultured DRG explants in the presence of NGF; under these conditions, IaPSNs die but NGF-dependent neurons survive. Loss of SADs had only a modest effect (12%) on axon outgrowth in these explants ( Figures 4H–4J). These findings indicate that SAD kinases are selectively required for axon growth in response to NT-3.