MHCI Immune Molecules Are Required For Developmental Synapse Elimination Of The Neuromuscular Junction (P2.337)

OBJECTIVE: Developmental synapse elimination in the vertebrate neuromuscular junction (NMJ) is required to establish the adult pattern of 1:1 nerve-muscle connectivity necessary to sequentially recruit muscles and vary the magnitude and speed of movements. However, the molecular events essential for this process remain elusive. Recent studies implicate a large family of immune proteins (>50 genes), members of the major histocompatibility complex class I (MHCI), as a requirement for synapse elimination in the visual system. Furthermore, these proteins are highly expressed in populations of motor neurons (MNs) that are vulnerable in MN diseases. This study suggests that MHCI proteins are molecular mediators in synapse elimination at the developing NMJ. METHODS/RESULTS: Our findings demonstrate that in mice lacking cell-surface expression of most MHCI proteins (MHCI-deficient), synapse elimination is disrupted in a subset of diaphragm NMJs at postnatal day 15 (P15), a period of development during which synapse elimination is normally complete. Multiply-innervated NMJs are still apparent in adulthood (P29-60) and aging (P365) MHCI-deficient animals, suggesting that the loss of MHCI may persistently disrupt synapse elimination. Subsequent studies have used mice with targeted genetic deletions of MHCI proteins H2-Kb and H2-Db, both previously recognized for their involvement in synapse remodeling of the visual system. At the diaphragm NMJ, a similar disruption in synapse elimination was observed in these mice compared to the MHCI-deficient mice used in initial studies, albeit at a lower percentage. This could indicate that H2-Kb and H2-Db work in concert with other MHCI family members to contribute to synapse elimination at the NMJ. CONCLUSIONS: These results suggest a novel role for MHCI in developmental synapse elimination of the NMJ. Ongoing research is focused on identifying the specific members of the MHCI family expressed at the NMJ, and required during synapse elimination. Understanding the role of MHCI in NMJ development may shed light on the underlying mechanisms of neuromuscular disorders. Study Supported by: Princeton Department of Molecular Biology. Disclosure: Dr. Tetruashvily has nothing to disclose. Dr. Boulanger has nothing to disclose.