The inositol pyrophosphates are essential for the development of mammals

He, Sining (2022) The inositol pyrophosphates are essential for the development of mammals. Doctoral thesis, University of East Anglia.

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Inositol polyphosphates, generated from a second messenger IP3 by a series of kinases, are a family of endogenous metabolites conserved across evolution. Inositol polyphosphates participate in diverse physiological activities, including insulin secretion, ubiquitination, apoptosis, cancer development. However, limited by techniques in imaging and measuring inositol phosphates in living cells, the spatial and temporal mechanism of these small molecules and their kinases remains poorly understood.

The kinases of IP6 (IP6Ks), including three mammalian homologs (IP6K1-3), are responsible for the production of inositol pyrophosphate (5-IP7, IP7) from the substrate IP6. IP6K1 and IP6K2 are widely spread in all tissues, while IP6K3 only exists in muscle and brain. Deletion of IP6K1 or IP6K2 reduces the accumulation of IP7 to some extent. Mice with IP6K1 deletion are male sterile, while IP6K2 deletion in mice does not show apparent phenotypes. However, little is known about the functions and mechanisms of IP7 in mammalian development. My research is to study the functions and mechanisms of IP7 in mammals by concurrently deleting IP6K1 and IP6K2 to deplete IP7 in mice, at least in many tissues of mice.

Results in this thesis demonstrate that concurrent IP6K1 and IP6K2 deletion in mice (Double knockout, DKO) leads to neonatal lethality associated with respiratory failure. Embryonic DKO lung has smaller size, reduced air space and

thicker alveolar walls, which are associated with the immaturity of type I and II lung epithelial cells and reduced expression of surfactant proteins. RNA-seq analysis reveal strong upregulation of innate immune response genes in DKO fetal lungs, which also display activation of the NF-kappa B and IRF3 pathways and increased levels of myeloid cells. Consistent with the findings, immune activation in fetal lung could be due to altered development of the hematopoietic system, which showed myeloid-biased differentiation in fetal livers. Finally, H2AX phosphorylation is upregulated in DKO livers and lungs, suggesting defective DNA damage repair.

Taken together, this study demonstrates that inositol pyrophosphates are essential for mouse viability, whose depletion leads to multiple developmental alterations in hematopoietic and pulmonary systems that may together cause respiratory failures.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Chris White
Date Deposited: 28 Apr 2022 12:57
Last Modified: 28 Apr 2022 12:57

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