Bone morphogenic proteins (BMPs) are a family of growth factors belonging to the transforming growth factor beta (TGF-ß) superfamily. At the Drosophila neuromuscular junction (NMJ), BMP signalling is involved in synapse development and possibly synaptic homeostasis through retrograde signalling. The LEM-domain protein MAN1 is located in the inner nuclear membrane and acts as a negative regulator of BMP signalling during wing vein formation in Drosophila. A deletion of the sequence coding for the C-terminus of MAN1 was generated, which we refer to as DMAN1.

In the present study, we investigate synaptic function in DMAN1 mutant animals. We performed two electrode voltage clamp (TEVC) measurements on muscles of wild type Drosophila larvae and of animals homozygous for the DMAN1 mutation. In the DMAN1 mutants, the amplitude of evoked excitatory postsynaptic currents (eEPSCs) was 17.0 3.0 nA (n=7), corresponding to 27% of the wild type amplitude (63.5 5.2 nA; n=7). The amplitude of miniature EPSCs (mEPSCs) was similar in wild type (1.3 nA 0.1; n=4) and DMAN1 mutants (1.3 nA 0.1; n=5). During high-frequency stimulation (6 pulses at 60 Hz), facilitation was more pronounced in DMAN1 mutants than in controls, indicating a reduction of release probability in DMAN1 mutants. Synaptic transmission could be partially rescued by either neuronal or muscular expression of MAN1 in the mutant background. Neuronal overexpression of MAN1 led to higher EPSC amplitudes than in wild type, while overexpression in muscles had no influence on EPSC amplitudes.

Our results suggest a crucial role for MAN1 in presynaptic function and probably retrograde BMP signalling at the Drosophila NMJ.