Shukla, Dhyanam, Gural, Brian M, Cauley, Edmund S, Roberts, Llion E, Karas, Brittany F, Cavallo, Luca, Turkalj, Luka, Moody, Sally A, Swan, Laura E 
ORCID: 0000-0002-6312-6263 and Manzini, M Chiara
(2022)
Duplicated zebrafish (<i>Danio rerio</i>) inositol phosphatases <i>inpp5ka</i> and <i>inpp5kb</i> diverged in expression pattern and function.
[Preprint]
Abstract
<jats:title>Abstract</jats:title><jats:p>One hurdle in the development of zebrafish models of human disease is the presence of multiple zebrafish orthologs resulting from whole genome duplication in teleosts. Mutations in Inositol polyphosphate 5-phosphatase K (<jats:italic>INPP5K</jats:italic>) lead to a syndrome characterized by variable presentation of intellectual disability, brain abnormalities, cataracts, muscle disease, and short stature. INPP5K is a phosphatase acting at position 5 of phosphoinositides to control their homeostasis and is involved in insulin signaling, cytoskeletal regulation, and protein trafficking. Previously, our group and others have replicated the human phenotypes in zebrafish knockdown models by targeting both <jats:italic>INPP5K</jats:italic> orthologs <jats:italic>inpp5ka</jats:italic> and <jats:italic>inpp5kb</jats:italic>. Here, we show that <jats:italic>inpp5ka</jats:italic> is the more closely related orthologue to human <jats:italic>INPP5K</jats:italic>. While both <jats:italic>inpp5ka</jats:italic> and <jats:italic>inpp5kb</jats:italic> mRNA expression levels follow a similar trend in the developing head, eyes, and tail, <jats:italic>inpp5ka</jats:italic> is much more abundantly expressed in these tissues than <jats:italic>inpp5kb. In situ</jats:italic> hybridization revealed a similar trend, also showing unique localization of <jats:italic>inpp5kb</jats:italic> in the pineal gland indicating different transcriptional regulation. We also found that <jats:italic>inpp5kb</jats:italic> has lost its catalytic activity against its preferred substrate, PtdIns(4,5)P<jats:sub>2</jats:sub>. Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss of <jats:italic>inpp5ka</jats:italic> alone can be targeted to recapitulate the human presentation. In addition, we show that the function of <jats:italic>inpp5kb</jats:italic> has diverged from <jats:italic>inpp5ka</jats:italic> and may play a novel role in the zebrafish.</jats:p>
| Item Type: | Preprint |
|---|---|
| Uncontrolled Keywords: | Biotechnology, Genetics, 1 Underpinning research, 2 Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 15 Mar 2023 09:44 |
| Last Modified: | 15 Mar 2024 04:41 |
| DOI: | 10.1101/2022.08.31.506059 |
| Open Access URL: | https://doi.org/10.1101/2022.08.31.506059 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169058 |
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