MEGF8, encoding a multidomain transmembrane protein, is highly conserved across species. Mutations in MEGF8 cause Carpenter syndrome, associated with learning disabilities, mental health issues, left-right patterning abnormalities, and congenital limb malformations like syndactyly [1,2,3,5]. It interacts with MGRN1, an E3 ubiquitin ligase, and is involved in BMP signaling which is crucial for sensory neuron development [2,4].

In mouse models, loss of Megf8 disrupts axon guidance in the peripheral nervous system, and leads to limb, heart, and left-right patterning defects similar to Bmp4 loss-of-function mice, suggesting its role in mediating BMP4 signaling [4]. Spatial and temporal deletion in mice showed that Megf8 was dispensable for cardiac organogenesis, but early deletion (E6.5) led to aortic arch artery defects indicating a latent effect on left-right patterning and heart development [8].

In Drosophila, the homolog dMegf8 is required for synapse development and function, and its mutants have motor coordination deficits and synaptic ultrastructure and neurotransmission defects [5]. The Drosophila homolog CG7466 is essential for larval development as homozygous mutants have disorganized denticle belts and die as larvae [6]. In honeybees, the microRNA ame-bantam-3p controls larval-pupal development by targeting megf8 [7].

In conclusion, MEGF8 is essential for multiple biological processes including synapse development, neuronal axon guidance, left-right patterning, and larval development. Mouse models, along with Drosophila and honeybee studies, have significantly contributed to understanding MEGF8's role in diseases like Carpenter syndrome and its associated phenotypes such as abnormal limb and heart development [1,2,3,4,5,6,7,8].