Murine Mind bomb1: its role in Notch and β-catenin signaling during embryonic development

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Rajendra, Rashmi

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Embryonic development is a complex process that requires the functioning of signaling pathways. Molecular interconnectivity is the hallmark of this process. Receptor – ligand interaction causes various downstream effects, which ultimately result in transcription activation, cellular specifications and differentiation. One of the most important pathways is Notch-Delta signaling. The proteins involved and their molecular functions are highly conserved. The last few years has seen a burst of research in various species, to elucidate various aspects of Notch signaling. This involves generating mutations and deletions in critical components of this pathway to ultimately identify normal cellular function. Among the proteins that regulate this pathway is a RING ubiquitin E3 ligase, Mind Bomb1, which is known to regulate Delta (DLL) protein levels within the cell by ubiquitination. With the goal of further understanding Notch signaling, a mouse knockout of Mind bomb1 was generated. We have shown that Mind bomb1 is essential for embryonic lethal as the knockout was lethal. Further we have shown that it displays a neurogenic phenotype, similar to Notch1 mutations. This study elucidates the disruption of Notch signaling in the mouse embryonic neuroepithelium. We further went on to identify changes in Notch1 protein activation in the absence Mind bomb1. We have shown a possible molecular connectivity with the β-catenin signaling pathway. We observe altered sub-cellular localization of β-catenin protein under conditions of aberrant Notch1 protein localization. These events have been observed in neuroepithelial cells that are undergoing premature neuronal differentiation. Taken together we can infer a requirement for Mind Bomb1 function in targeting Notch signaling directly and possibly β-catenin signaling indirectly. We have also generated a conditional knockout allele of Mind bomb1. This allele can be used for tissue-, temporal- or specific gene-regulated deletion of Mind bomb1. Further analyses using both the null and the conditional alleles of Mind bomb1 will help ascertain highly conserved cellular mechanisms.