Grb10a knockdown in Danio rerio during early life alters growth and cardiometabolic function associated with a remodelled transcriptome

Embryonic growth trajectory is a risk factor for chronic metabolic and cardiovascular disorders and influences birth weight and early post-natal weight gain in humans. Grb10 is a negative regulator of the main pathways driving embryonic growth. Grb10 knock-out in mammals increases insulin sensitivity and growth trajectory. This study has now investigated the long-term cardiometabolic consequences and associated transcriptomic profiles of morpholino induced early life disruption in grb10a expression in Danio rerio. Transient knockdown increased embryonic growth (+7 %) and metabolic rate (+25 %), while decreasing heart rate (-50 %) in early life. Juvenile growth and respiratory rate were also elevated (+30 % and 7-fold increase respectively). This was associated with permanent remodelling the transcriptional landscape. Multiple growth-related pathways were dysregulated. This study indicates that zebrafish are a suitable model for life-long investigation of the link between early growth and later life disease risk. Pooled samples (n=5) were generated to form each treatment group. Treatment group 1 = Standard control oligonucleotide targeting human beta globin [SC] and treatment group 2 = the knock down (KD) Morpholino- a modified antisense oligonucleotide targeting the splice donor sites of zebrafish grb10a coding exon three (e3i3). All groups were analysed at 5, 10, 15, 20, and 30 days post fertilisation (dpf), with three repeats per group.