Teleosts and tetrapods have evolved different splice patterns to generate their membrane-bound IgM. In the tetrapod lineage, the first transmembrane exon is spliced to an internal cryptic site located close to the end of the fourth constant exon. Because teleosts lack this site they use the regular 3-splice site of the CH3 exon instead. We characterized the mum splicing patterns in a Chondrostean, the Siberian sturgeon. We observed a surprising diversity of splice patterns, the TM1 exon being spliced to a cryptic site at the end of CH4, to a cryptic site in CH3 or to the 3-end of CH1. These different pathways lead to mIGHM transcripts encoding four, two or one complete C-domain(s), respectively. The short variant CH1-TM1 was found only in VH2 positive transcripts, while the two other variants were observed for IgHM transcripts expressing all VH families. These results shed light on the evolution of IgM splicing pathways.
Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.
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