Loss of Elp1 disrupts trigeminal ganglion neurodevelopment in a model of Familial Dysautonomia

Familial Dysautonomia (FD) is a sensory and autonomic neuropathy caused by a mutation in Elongator complex protein 1 (ELP1). FD patients have small trigeminal nerves and impaired perception of facial pain and temperature. These signals are relayed by nociceptive neurons in the trigeminal ganglion, a structure comprised of both neural crest- and placode-derived cells. Mice lacking Elp1 in neural crest derivatives (Elp1 CKO) are born with smaller trigeminal ganglia, suggesting Elp1 is important for trigeminal ganglion development, yet the function of Elp1 in this context is unknown. We demonstrate Elp1 expression in both neural crest- and placode-derived trigeminal neurons, which our data suggest give rise to primarily TrkA- and TrkB/C-expressing neurons, respectively. While Elp1 is not required for initial trigeminal ganglion formation, Elp1 CKO trigeminal neurons exhibit abnormal axon outgrowth and decreased target innervation. Developing nociceptors that express the receptor TrkA are especially vulnerable to Elp1 loss. TrkA expression is decreased in Elp1 CKO trigeminal nerve endings, coinciding with increased cell death. Subsequently, fewer TrkA neurons are present in the Elp1 CKO trigeminal ganglion, indicating Elp1 supports the target innervation and survival of trigeminal nociceptors. These findings explain the loss of facial pain and temperature sensation in FD.

Region Specific Central Arbor Morphologies of Nociceptive Afferents Develop Independently of Their Peripheral Target Innervation

ABSTRACTFunctionally important regions of sensory maps are overrepresented in the sensory pathways and cortex, but the underlying developmental mechanisms are not clear. In the spinal cord dorsal horn (DH), we recently showed that paw innervating Mrgprd+ non-peptidergic nociceptors display distinctive central arbor morphologies that well correlate with increased synapse transmission efficiency and heightened sensitivity of distal limb skin. Given that peripheral and central arbor formation of Mrgprd+ neurons co-occurs around the time of birth, we tested whether peripheral cues from different skin areas and/or postnatal reorganization mechanisms could instruct this somatotopic difference among central arbors. We found that, while terminal outgrowth/refinement occurs during early postnatal development in both the skin and the DH, postnatal refinement of central terminals precedes that of peripheral terminals. Further, we used single-cell ablation of Ret to genetically disrupt epidermal innervation of Mrgprd+ neurons and revealed that the somatotopic difference among their central arbors was unaffected by this manipulation. Finally, we saw that region-specific Mrgprd+ central terminal arbors are present from the earliest postnatal stages, before skin terminals are evident. Together, our data indicate that region-specific organization of Mrgprd+ neuron central arbors develops independently of peripheral target innervation and is present shortly after initial central terminal formation, suggesting that either cell-intrinsic and/or DH local signaling may establish this somatotopic difference.