TABLE 4:
Phenotypes of mice with mutations/deletions of ARF family GTPases.
| GTPase | Conventional knockout | Conditional knockout | Reference |
|---|---|---|---|
| ARF1 | Embryonically lethal (E5.5) | — | Hayakawa et al. (2014) |
| ARF4 | Postnatal deletion (Arf4flox/CagCreER):Reduced viability; reduced size of the pancreas; yellowish feces in lower intestine; hair turned from black to gray | Pearring et al. (2017) | |
| Photoreceptor cells (Arf4flox/iCre75):Normal rhodopsin localization; no retinal degeneration | Pearring et al. (2017) | ||
| Kidney (Arf4flox/HoxB7Cre):No cystic disease | Pearring et al. (2017) | ||
| Pancreas (Arf4flox/CagCreER):Degeneration of exocrine pancreas; infiltration of adipocytes in exocrine pancreas; normal islet size and organization | Pearring et al. (2017) | ||
| ARF6 | Embryonically lethal (midgestation); smaller liver with progressive apoptosis; defective hepatic cord formation | — | Suzuki et al. (2006) |
| ARF6 | Endothelial cells (Arf6flox/Tie2-Cre):Reduced tumor angiogenesis via impaired HGF-induced endothelial β1-integrin recycling | Hongu et al. (2015) | |
| Neuronal cells (Arf6flox/Nestin-Cre):Smaller size of fimbria of hippocampus and corpus callosum; impaired oligodendrocyte myelination in the hippocampal fimbria and the corpus callosum during development, due to reduced secretion of fibroblast growth factor-2 | Akiyama et al. (2014) | ||
| Platelets (Arf6flox/PF4-Cre):Impaired αIIbβ3-integrin trafficking resulting in reduced fibrinogen uptake and storage | Huang et al. (2016) | ||
| Podocyte specific (Arf6flox-Nphs2-Cre):Normal kidney developmentIn model of acute podocyte effacement: protection from podocyte effacementIn model for immune complex–mediated injury: aggravated proteinuria | Lin et al. (2017) | ||
| ARL3 | Early death (3 wk of age); abnormal development of renal, hepatic, and pancreatic epithelial tubule structures; abnormal epithelial cell proliferation and cyst formation; photoreceptor degeneration (at P14) | — | Schrick et al. (2006) |
| Retina specific (Arl3flox/Six3-Cre):Impaired ciliogenesis; no formation of connecting cilia and outer segments; degeneration of retina at 2 mo; inability of retina to respond to light rapidly | Hanke-Gogokhia et al. (2016) | ||
| Rod photoreceptor specific (Arl3flox/iCre75):Photopic responses started to decline at the age of 1 mo; degeneration of rods and cones at 2 mo; decline of retinal thicknessTrafficking deficiencies of lipidated phototransduction proteins, e.g., farnesylated rhodopsin kinase (GRK1) | Hanke-Gogokhia et al. (2016) | ||
| ARL4 | Reduction of testis weight (30%) and sperm count (60%) without affecting fertility | — | Schurmann et al. (2002) |
| ARL6 (BBS3) | Development of BBS-associated phenotypes: retinal degeneration, male infertility, loss of sperm flagella, severe hydrocephalus, thinning of the cerebral cortex; reduced size of hippocampus and corpus striatum, reduced number and misshaping of ependymal cell cilia, increased body fat | — | Zhang et al. (2011) |
| ARL13B(a GEF of ARL3) | Hennin (hnn) mutation (ENU-induced mutation) corresponding to Arl3 null allele:Embryonically lethal; at ED 9.5, open neural tube in the head, caudal spinal cord, and randomized heart looping; at ED 14, abnormal eyes and axial polydactylyNodal cilia half the normal length; abnormal structure of the axonemeSpecific disruption of the Sonic hedgehog (Shh) signaling pathway | Caspary et al. (2007) | |
| Kidney specific (Arl13Bflox-Ksp-Cre):Defective cilia biogenesis and rapid kidney cyst formation due to an overproliferation followed by fibrosis; increased kidney-to-body weight ratio; mutant mice dead at around P60 | Li et al. (2016) | ||
| Retina specific (Arl13Bflox/Six3-Cre):Absence of outer segments of the retina (starting at P6); photoreceptor rhodopsin: failure to form mature transition zones and outer segments and rapid degeneration; normal docking of basal bodies of photoreceptors to cell membranes | Hanke-Gogokhia et al. (2017) | ||
| Tamoxifen-inducible Cre/loxP recombination (Arl13Bflox-CAG-CreER) at 1 mo of age:Destabilization of axonemes and transition zones, leading to progressive photoreceptor degeneration; impairment of anterograde intraflagellar transport (IFT) due to marked reduction of IFT88 protein at basal bodies;impaired retinogenesis, including early postnatal proliferation of retinal progenitor cells, development of photoreceptor cilia, and morphogenesis of photoreceptor outer segment; mislocalization of rhodopsin, prenylated phosphodiesterase-6 (PDE6), and IFT88 | Hanke-Gogokhia et al. (2017);Dilan et al. (2018) | ||
| Tamoxifen-inducible Cre/loxP recombination (Arl13Bflox-CAGG-CreER) at postnatal day 4:Mutant mice smaller than the control littermates; ∼two-thirds dead from cystic kidneys between P27 and P51Normal cerebellar size and foliation | Bay et al. (2018) | ||
| ARFRP1 | Embryonically lethal; apoptotic epiblast cells within ectoderm at ED 6.0 and 7.0Mistargeting of E-cadherin to intracellular compartments | Mueller et al. (2002);Zahn et al. (2008) | |
| Intestine specific (Arfrp1flox/villin-Cre):Lower abundance of E-cadherin at the lateral membrane of the cell surface of crypts and villi (E-cadherin is associated with intracellular membranes); marked growth retardation due to impaired lipid uptake; impaired chylomicron lipidation and reduced release of ApoA-I | Zahn et al. (2008);Jaschke et al. (2012) | ||
| Liver specific (Arfrp1flox/alb-Cre):Early growth retardation due to reduced secretion of hepatic insulin-like growth factor 1 (IGF1); decreased glucose transport and glycogen storage; intracellular retention of glucose transporter GLUT2Impaired VLDL lipidation resulting in reduced plasma triglyceride levels in the fasted state | Hesse et al. (2012) | ||
| Adipocyte specific (Arfrp1flox/ap2-Cre):Nearly abolished triglyceride storage in adipocytes, smaller lipid droplets, impaired lipid droplet fusion, and enhanced lipolysisImpaired sorting of the glucose transporter GLUT4 to intracellular storage compartment | Hommel et al. (2010);Hesse et al. (2010) | ||
| Inducible adipocyte specific Tamoxifen-inducible Cre/loxP recombination Arfrp1flox/CreERT2):Impaired secretion of adiponectin and recycling of insulin receptor; decreased insulin signaling in adipose tissue and liver. | Rodiger et al. (2018) |
Indicated are the ARF and ARL proteins deleted either as whole-body knockout (conventional knockout) or in a cell-type or tissue-specific manner, including inducible deletions (conditional knockout). E, embryonic day; ENU, N-ethyl-N-nitrosourea; HGF, hepatocyte growth factor; P, postnatal day; VLDL, very low density lipoprotein.