Kalrnplays key roles within and outside of the nervous system

Abstract

BackgroundThe human KALRN gene, which encodes a complex, multifunctional Rho GDP/GTP exchange factor, has been linked to cardiovascular disease, psychiatric disorders and neurodegeneration. Examination of existing Kalrn knockout mouse models has focused only on neuronal phenotypes. However, Kalirin was first identified through its interaction with an enzyme involved in the synthesis and secretion of multiple bioactive peptides, and studies in C.elegans revealed roles for its orthologue in neurosecretion.ResultsWe used a broad array of tests to evaluate the effects of ablating a single exon in the spectrin repeat region of Kalrn (KalSRKO/KO); transcripts encoding Kalrn isoforms containing only the second GEF domain can still be produced from the single remaining functional Kalrn promoter. As expected, KalSRKO/KO mice showed a decrease in anxiety-like behavior and a passive avoidance deficit. No changes were observed in prepulse inhibition of acoustic startle or tests of depression-like behavior. Growth rate, parturition and pituitary secretion of growth hormone and prolactin were deficient in the KalSRKO/KO mice. Based on the fact that a subset of Kalrn isoforms is expressed in mouse skeletal muscle and the observation that muscle function in C.elegans requires its Kalrn orthologue, KalSRKO/KO mice were evaluated in the rotarod and wire hang tests. KalSRKO/KO mice showed a profound decrease in neuromuscular function, with deficits apparent in KalSR+/KO mice; these deficits were not as marked when loss of Kalrn expression was restricted to the nervous system. Pre- and postsynaptic deficits in the neuromuscular junction were observed, along with alterations in sarcomere length.ConclusionsMany of the widespread and diverse deficits observed both within and outside of the nervous system when expression of Kalrn is eliminated may reflect its role in secretory granule function and its expression outside of the nervous system.

The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts

“…To examine the potential role of Kalirin in the regulation of bone mass and bone geometry, we performed micro-CT analysis of Kalirin knockout (Kal-KO) which lack exon 13 of the Kalrn gene [12]. Since exon 13 of the Kalrn gene encodes the spectrin repeat common to all major Kalirin isoforms, as well as several N-terminal splice variants, global Kal-KO (Kal −/− ) mice lack detectable Kalirin-7, Kalirin-9 and Kalirin-12 in all tissues [17,18].…”

“…Kalirin spectrin repeat knockout (Kal-KO) mice were generated and validated [12], and a colony was established at Indiana University School of Dentistry. All mouse work was carried out under IACUC protocol DS000885R.…”

“…Kalirin has been shown to play a role in cytoskeletal remodeling, synapse and dendritic spine morphogenesis and extension, secretory granule maturation and plasticity of dendritic spines in neuronal cells [7–11]. Recently, Kalirin has also been shown to be important in neuromuscular function [7–12]. Given that the activity of Rho-GTPases is critical for the function of osteoclasts and osteoblasts, we hypothesized that Kalirin may be important for the regulation of bone cells and bone mass.…”

Using Kalirin conditional knockout mice to distinguish its role in dopamine receptor mediated behaviors

“…5) [7, 52]. Interestingly, selective loss of Kalirin isoforms in POMC-Cre mice produces a similar reduction in anxiety-like behavior [43].…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…In adults, Kalirin-7 is the major isoform in mature neurons, whereas Kalirin-9 and Kalirin-12 are primarily found at lower levels in peripheral tissues (87). Genetic disruption of Kalirin-7 reduced spine density and induced several motor and behavior deficits (71,(147)(148)(149). Depletion of Kalirin-7 also impairs synaptic plasticity, probably through alteration of glutamate receptors and Rac1 signaling (150,151).…”