Biology subjects

Moorwood, K.

Publications and source records attributed to Moorwood, K..

4 recordsLinked to original sources

bioRxiv2024

Grb7, Grb10 and Grb14, encoding the growth factor receptor-bound 7 family of signalling adaptor proteins have overlapping functions in the regulation of fetal growth and post-natal glucose metabolism

BackgroundThe growth factor receptor bound 7 (Grb7) family of signalling adaptor proteins comprises Grb7, Grb10 and Grb14. Each can interact with the insulin receptor and other receptor tyrosine kinases, where Grb10 and Grb14 inhibit insulin receptor activity. In cell culture studies they mediate functions including cell survival, proliferation, and migration. Mouse knockout (KO) studies have revealed physiological roles for Grb10 and Grb14 in glucose-regulated energy homeostasis. Both Grb10 KO and Grb14 KO mice exhibit increased insulin signalling in peripheral tissues, with increased glucose and insulin sensitivity and a modestly increased ability to clear a glucose load. In addition, Grb10 strongly inhibits fetal growth such that at birth Grb10 KO mice are 30% larger by weight than wild type littermates. ResultsHere, we generate a Grb7 KO mouse model. We show that during fetal development the expression patterns of Grb7 and Grb14 each overlap with that of Grb10. Despite this, Grb7 and Grb14 did not have a major role in influencing fetal growth, either alone or in combination with Grb10. At birth, in most respects both Grb7 KO and Grb14 KO single mutants were indistinguishable from wild type, while Grb7:Grb10 double knockout (DKO) were near identical to Grb10 KO single mutant and Grb10:Grb14 DKO mutants slightly smaller. In the developing kidney Grb7 had a subtle positive influence on growth. An initial characterisation of Grb7 KO adult mice revealed sexually dimorphic effects on energy homeostasis, with females having significantly smaller white adipose tissue (WAT) depots and an enhanced ability to clear glucose from the circulation, compared to wild type littermates. Males had elevated fasted glucose levels with a trend towards smaller WAT depots, without improved glucose clearance. ConclusionsGrb7 and Grb14 do not have significant roles as inhibitors of fetal growth, unlike Grb10, and instead Grb7 may promote growth of the developing kidney. In adulthood, Grb7 contributes subtly to glucose mediated energy homeostasis, raising the possibility of redundancy between all three adaptors in physiological regulation of insulin signalling and glucose handling.

developmental biology↗

bioRxiv2024

Imprinted Grb10, encoding growth factor receptor bound protein 10, regulates fetal growth independently of the insulin-like growth factor type 1 receptor (Igf1r) and insulin receptor (Insr) genes

BackgroundOptimal size at birth dictates perinatal survival and long-term risk of developing common disorders such as obesity, type 2 diabetes and cardiovascular disease. The imprinted Grb10 gene encodes a signalling adaptor protein capable of inhibiting receptor tyrosine kinases, including the insulin receptor (Insr) and insulin-like growth factor type 1 receptor (Igf1r). Grb10 restricts fetal growth such that Grb10 knockout (KO) mice are at birth some 25-35% larger than wild type. Using a mouse genetic approach, we test the widely held assumption that Grb10 influences growth through interaction with Igf1r, which has a highly conserved growth promoting role. ResultsShould Grb10 interact with Igf1r to regulate growth Grb10:Igf1r double mutant mice should be indistinguishable from Igf1r KO single mutants, which are around half normal size at birth. Instead, Grb10:Igf1r double mutants were intermediate in size between Grb10 KO and Igf1r KO single mutants, indicating additive effects of the two signalling proteins having opposite actions in separate pathways. Some organs examined followed a similar pattern, though Grb10 KO neonates exhibited sparing of the brain and kidneys, whereas the influence of Igf1r extended to all organs. An interaction between Grb10 and Insr was similarly investigated. While there was no general evidence for a major interaction for fetal growth regulation, the liver was an exception. The liver in Grb10 KO mutants was disproportionately overgrown with evidence of excess lipid storage in hepatocytes, whereas Grb10:Insr double mutants were indistinguishable from Insr single mutants or wild types. ConclusionsGrb10 acts largely independently of Igf1r or Insr to control fetal growth and has a more variable influence on individual organs. Only the disproportionate overgrowth and excess lipid storage seen in the Grb10 KO neonatal liver can be explained through an interaction between Grb10 and the Insr. Our findings are important for understanding how positive and negative influences on fetal growth dictate size and tissue proportions at birth.

developmental biology↗

bioRxiv2020

Mice carrying paternal knockout of imprinted Grb10 do not show compulsive behaviours

Mice lacking paternal expression of imprinted Grb10 show a number of social behaviour deficits, including an enhanced allogrooming phenotype. However, this could also index compulsive behaviour, and the increased whisker barbering seen in Grb10+/p mice has been suggested to be indicative of a trichotillomania-type behaviour. Here we test whether compulsive behaviour is a more general phenotype in Grb10+/p mice by examining marble burying. We also examined the mice for potentially confounding anxiety phenotypes using the elevated plus maze (EPM). Grb10+/p mice showed no difference from wild-type littermate controls on any measure in the marble burying test at any age. However, Grb10+/p mice were more willing to enter, spend time on, and head-dip on the open arm of the EPM than wild-type mice. These data suggest that Grb10+/p mice are not generally more compulsive, and that the enhanced allogrooming is probably indicative of altered social behaviour. Furthermore, the altered behaviours seen on the EPM adds to other published findings suggesting that Grb10 has a role in mediating risk-taking.

animal behavior and cognition↗

bioRxiv2018

Detailed analysis of paternal knockout Grb10 mice suggests effects on social stability, rather than social dominance

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is currently recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10+/p mice. Moreover, the original study examined tube-test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10+/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences, and tested cohorts aged 2, 6, and 10 months to examine any developments related to age. We found group-housed Grb10+/p mice do not show evidence of enhanced social dominance, but cages containing Grb10+/p and wildtype mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10+/p mice should focus on social stability, rather than dominance per se.

animal behavior and cognition↗