Growth Defects and Impaired Cognitive–Behavioral Abilities in Mice with Knockout for Eif4h, a Gene Located in the Mouse Homolog of the Williams-Beuren Syndrome Critical Region

Abstract

Protein synthesis is a tightly regulated, energy-consuming process. The control of mRNA translation into protein is fundamentally important for the fine-tuning of gene expression; additionally, precise translational control plays a critical role in many cellular processes, including development, cellular growth, proliferation, differentiation, synaptic plasticity, memory, and learning. Eukaryotic translation initiation factor 4h (Eif4h) encodes a protein involved in the process of protein synthesis, at the level of initiation phase. Its human homolog, WBSCR1, maps on 7q11.23, inside the 1.6 Mb region that is commonly deleted in patients affected by the Williams-Beuren syndrome, which is a complex neurodevelopmental disorder characterized by cardiovascular defects, cerebral dysplasias and a peculiar cognitive-behavioral profile. In this study, we generated knockout mice deficient in Eif4h. These mice displayed growth retardation with a significant reduction of body weight that began from the first week of postnatal development. Neuroanatomical profiling results generated by magnetic resonance imaging analysis revealed a smaller brain volume in null mice compared with controls as well as altered brain morphology, where anterior and posterior brain regions were differentially affected. The inactivation of Eif4h also led to a reduction in both the number and complexity of neurons. Behavioral studies revealed severe impairments of fear-related associative learning and memory formation. These alterations suggest that Eif4h might contribute to certain deficits associated with Williams-Beuren syndrome.

Prenatal phenotype of Williams–Beuren syndrome and of the reciprocal duplication syndrome

“…IUGR has also been reported in WBS adult patients, the mean decrease in adult height compared to target height is nearly 10 cm and head circumference can be also reduced [31,32]. Recently, growth defects and impaired cognitive-behavioral abilities have been observed in Eif4h null mice, whose human homolog maps in WBSCR1 region [33]. We hypothesize that IUGR can be an early indication for the suspicion of WBS that should be prenatally investigated in addition to the other chromosomal causes (e.g.,: 4p16.3, 6q24-q25, and 15q26-qter microdeletions and uniparental disomy of chromosome 7) after a normal karyotype.…”

The developmental and genetic basis of ‘clubfoot’ in the peroneal muscular atrophy mutant mouse

“…S9). Eif4h encodes a neurally expressed translation initiation factor responsible for modulating normal neuronal number and complexity in the CNS (Capossela et al, 2012).…”

Key contribution of eIF4H-mediated translational control in tumor promotion

“…eIF4H-deficient knockout mouse harbors growth defects, body weight loss, brain abnormalities, altered neuronal morphology and several behavior anomalies. This demonstrates that eIF4H depletion may contribute to certain deficiencies associated with Williams-Beuren Syndrome [ 23 ].…”