Phenotypes associated with this allele

• Allele Symbol: Tyro3^tm1Grl
• Allele Name: targeted mutation 1, Greg Lemke
• Allele ID: MGI:2387762
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tyro3^tm1Grl/Tyro3^tm1Grl	involves: 129S1/Sv * 129X1/SvJ	MGI:2654779
cx2	Mertk^tm1Grl/Mertk^tm1Grl Tyro3^tm1Grl/Tyro3^tm1Grl	involves: 129S1/Sv * 129X1/SvJ	MGI:2654784
cx3	Axl^tm1Grl/Axl^tm1Grl Mertk^tm1Grl/Mertk^tm1Grl Tyro3^tm1Grl/Tyro3^tm1Grl	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:2654781
cx4	Axl^tm1Grl/Axl^tm1Grl Tyro3^tm1Grl/Tyro3^tm1Grl	involves: 129S1/Sv * 129X1/SvJ * C57BL/6J	MGI:2654783

Genotype
MGI:2654779

hm1

• Allelic Composition: Tyro3^tm1Grl/Tyro3^tm1Grl
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

abnormal seizure response to inducing agent ( J:54681 )

• activity-induced seizures are observed in mutants more than 7 months old

nervous system

abnormal seizure response to inducing agent ( J:54681 )

• activity-induced seizures are observed in mutants more than 7 months old

vision/eye

vision/eye phenotype ( J:116526 )

N • retinas appear normal with no photoreceptor degeneration

reproductive system

reproductive system phenotype ( J:133455 )

N • mutant Sertoli cells exhibit normal phagocytosis of apoptotic spermatogenic cells relative to wild-type controls, as determined by lipid droplet formation using Oil Red O staining

cardiovascular system

cardiovascular system phenotype ( J:198769 )

N • mice exhibit normal vascular permeability in the liver

Genotype
MGI:2654784

cx2

• Allelic Composition: Mertk^tm1Grl/Mertk^tm1Grl; Tyro3^tm1Grl/Tyro3^tm1Grl
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

endocrine/exocrine glands

small testis ( J:54681 )

♂

reproductive system

small testis ( J:54681 )

♂

vagina atresia ( J:142166 )

♀ • 3.7% of females exhibit vaginal atresia

abnormal spermatogenesis ( J:54681 )

♂

oligozoospermia ( J:54681 )

♂ • reduced amount of mature sperm in the epididymis

decreased Sertoli cell phagocytosis ( J:133455 )

♂ • double mutant Sertoli cells show a ~35% decrease in phagocytosis of apoptotic spermatogenic cells relative to wild-type controls, as determined by lipid droplet formation using Oil Red O staining; this reduction is similar to that observed in Mertk^tm1Grl singly mutant Sertoli cells

cellular

oligozoospermia ( J:54681 )

♂ • reduced amount of mature sperm in the epididymis

Genotype
MGI:2654781

cx3

• Allelic Composition: Axl^tm1Grl/Axl^tm1Grl; Mertk^tm1Grl/Mertk^tm1Grl; Tyro3^tm1Grl/Tyro3^tm1Grl
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

cardiovascular system

abnormal blood vessel morphology ( J:54681 )

• increased apoptosis and cellular degeneration in vessel walls

internal hemorrhage ( J:70420 )

• hemorrhage is observed in several tissues, including the brain, and is associated with autoimmunity

growth/size/body

enlarged spleen ( J:54681 , J:70420 )

• spleens grow at an elevated rate compared to wild-type starting at 4 weeks of age, such that at 1 year of age, spleen weight is 10 times that of wild-type (J:70420)

cellular

azoospermia ( J:54681 )

♂ • progressive death of differentiating germ cells resulting in an absence of mature sperm

increased apoptosis ( J:54681 )

• an increase in apoptosis is observed in the hippocampus, cerebellum, neocortex, the epithelium of the prostate, the granulosa cells of the ovary, the parenchyma of the liver, the walls of blood vessels, and the spleen

increased granulosa cell apoptosis ( J:54681 )

♀ • increased apoptosis of granulosa cells

increased splenocyte apoptosis ( J:54681 )

• spleen is populated by apoptotic cells

increased brain apoptosis ( J:54681 )

• increased apoptosis in the hippocampus, cerebellum and neocortex

increased B cell proliferation ( J:70420 )

increased T cell proliferation ( J:70420 )

endocrine/exocrine glands

increased granulosa cell apoptosis ( J:54681 )

♀ • increased apoptosis of granulosa cells

abnormal prostate gland epithelium morphology ( J:54681 )

♂ • the epithelium of the prostate exhibits altered histology, increased apoptosis and cellular degeneration

small endometrial glands ( J:142166 )

♀ • endometrial glands are significantly reduced in females with vaginal atresia

abnormal seminiferous tubule morphology ( J:54681 )

♂ • cellular organization of the seminiferous tubules is perturbed

small testis ( J:54681 )

♂ • approximately one-third the size of wild-type testes

hematopoietic system

increased splenocyte apoptosis ( J:54681 )

• spleen is populated by apoptotic cells

enlarged spleen ( J:54681 , J:70420 )

• spleens grow at an elevated rate compared to wild-type starting at 4 weeks of age, such that at 1 year of age, spleen weight is 10 times that of wild-type (J:70420)

increased lymphocyte cell number ( J:70420 )

• hyperproliferation of B and T cells, leading to ectopic colonies of lymphocytes in most organs

abnormal B cell activation ( J:70420 )

• B cells are constituitively activated

increased B cell proliferation ( J:70420 )

abnormal T cell activation ( J:70420 )

• T cells are constituitively activated

increased T cell proliferation ( J:70420 )

abnormal macrophage physiology ( J:70420 )

• cultured macrophages produce excessive amounts of IL-12 and exhibit a 3.5-fold increase in generalized phagocytosis

immune system

increased splenocyte apoptosis ( J:54681 )

• spleen is populated by apoptotic cells

enlarged spleen ( J:54681 , J:70420 )

• spleens grow at an elevated rate compared to wild-type starting at 4 weeks of age, such that at 1 year of age, spleen weight is 10 times that of wild-type (J:70420)

increased lymphocyte cell number ( J:70420 )

• hyperproliferation of B and T cells, leading to ectopic colonies of lymphocytes in most organs

abnormal T cell activation ( J:70420 )

• T cells are constituitively activated

increased T cell proliferation ( J:70420 )

increased circulating tumor necrosis factor level ( J:70420 )

• serum levels of TNFalpha are more than doubled in mutants 1 hour after LPS injection compared to wild-type

enlarged lymph nodes ( J:70420 )

• notable in the submaxillary, popliteal, and mesenteric nodal stations

abnormal professional antigen presenting cell physiology ( J:70420 )

• chronic hyperactivation of antigen presenting cells

abnormal B cell activation ( J:70420 )

• B cells are constituitively activated

increased B cell proliferation ( J:70420 )

abnormal macrophage physiology ( J:70420 )

• cultured macrophages produce excessive amounts of IL-12 and exhibit a 3.5-fold increase in generalized phagocytosis

abnormal susceptibility to autoimmune disorder ( J:70420 )

• all mutants develop autoimmunity resulting from chronic hyperactivation of antigen-presenting cells

increased autoantibody level ( J:70420 )

• mutants exhibit autoantibodies to varous collagens, to phospholipids, cardiolipin, phosphatidylinositol, and phosphatidylethanolamine

increased anti-double stranded DNA antibody level ( J:70420 )

joint inflammation ( J:70420 )

• inflammation and lymphocyte invasion of joints is seen at 6 months of age, leading to swollen joints

liver/biliary system

liver degeneration ( J:54681 )

• increased apoptosis and cellular degeneration in parenchyma

reproductive system

increased granulosa cell apoptosis ( J:54681 )

♀ • increased apoptosis of granulosa cells

abnormal prostate gland epithelium morphology ( J:54681 )

♂ • the epithelium of the prostate exhibits altered histology, increased apoptosis and cellular degeneration

abnormal seminiferous tubule morphology ( J:54681 )

♂ • cellular organization of the seminiferous tubules is perturbed

small testis ( J:54681 )

♂ • approximately one-third the size of wild-type testes

abnormal uterus morphology ( J:142166 )

♀ • uterine wall of females with vaginal atresia is thinner

small endometrial glands ( J:142166 )

♀ • endometrial glands are significantly reduced in females with vaginal atresia

enlarged uterus ( J:142166 )

♀ • in females with vaginal atresia

vagina atresia ( J:142166 )

♀ • 16% of females exhibit vaginal atresia

abnormal spermatogenesis ( J:54681 )

♂ • progressive depletion of germ cells; release of the few mature sperm that are produced is delayed beyond the normal stage of release (tubule stage VIII)

azoospermia ( J:54681 )

♂ • progressive death of differentiating germ cells resulting in an absence of mature sperm

decreased Sertoli cell phagocytosis ( J:133455 )

♂ • triple mutant Sertoli cells show a 7.6-fold reduction in phagocytosis of apoptotic spermatogenic cells relative to wild-type controls, as determined by lipid droplet formation using Oil Red O staining

♂ • triple mutant Sertoli cells show a 4-fold reduction in phagocytosis of apoptotic spermatogenic cells relative to Mertk^tm1Grl singly mutant Sertoli cells

♂ • notably, triple mutant Sertoli cells bind apoptotic spermatogenic cells with an average of 0.8 per Sertoli cell, whereas wild-type and Mertk^tm1Grl singly mutant Sertoli cells bind to apoptotic germ cells similarly with 2.8 and 2.6 per Sertoli cells, respectively

♂ • however, triple mutant Sertoli cells show normal ingestion of latex beads relative to wild-type Sertoli cells, indicating that the phagocytic deficit is specific to the ingestion of apoptotic spermatogenic cells

reduced female fertility ( J:54681 , J:70420 )

♀ (J:54681)

♀ • most females do not carry pregnanices to term (J:70420)

male infertility ( J:54681 )

♂

vision/eye

retina cone cell degeneration ( J:54681 )

retina rod cell degeneration ( J:54681 )

blindness ( J:54681 )

• mutants are blind due to postnatal degeneration of retinal rods and cones

nervous system

increased brain apoptosis ( J:54681 )

• increased apoptosis in the hippocampus, cerebellum and neocortex

abnormal hippocampus morphology ( J:54681 )

• hippocampus shows altered histology, increased apoptosis, and cellular degeneration

abnormal cerebral cortex morphology ( J:54681 )

• neocortex shows altered histology, increased apoptosis, and cellular degeneration

abnormal cerebellum morphology ( J:54681 )

• cerebellum exhibits altered histology, increased apoptosis, and cellular degeneration

retina cone cell degeneration ( J:54681 )

retina rod cell degeneration ( J:54681 )

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:70420 )

• serum levels of TNFalpha are more than doubled in mutants 1 hour after LPS injection compared to wild-type

abnormal thrombosis ( J:70420 )

• thromboses are seen in several tissues such as the brain and are associated with autoimmunity

abnormal brain thrombosis ( J:70420 )

skeleton

joint inflammation ( J:70420 )

• inflammation and lymphocyte invasion of joints is seen at 6 months of age, leading to swollen joints

integument

skin lesions ( J:70420 )

• a manifestation of autoimmunity

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autoimmune disease		DOID:417	OMIM:109100	J:70420

Genotype
MGI:2654783

cx4

• Allelic Composition: Axl^tm1Grl/Axl^tm1Grl; Tyro3^tm1Grl/Tyro3^tm1Grl
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6J

reproductive system

reproductive system phenotype ( J:133455 )

N • double mutant Sertoli cells exhibit normal phagocytosis of apoptotic spermatogenic cells relative to wild-type controls, as determined by lipid droplet formation using Oil Red O staining

small testis ( J:54681 )

♂

abnormal spermatogenesis ( J:54681 )

♂ • defects less severe than in mice homozygous for both Mertk^tm1Grl and Tyro3^tm1Grl

delayed sexual maturation ( J:141251 )

♀ • first estrus, which is dependent on a normal GnRH-induced LH surge mechanism, is delayed

♀ • in contrast, onset of vaginal opening is normal

delayed estrous cycle ( J:141251 )

♀ • double homozygous females display a delayed first estrus by 4 days relative to wild-type controls

♀ • however, double homozygous females are fertile and deliver healthy litters of normal-size pups

short diestrus ( J:141251 )

♀ • at 2 months of age, many double homozygous females exhibit decreased diestrous phase lengths relative to wild-type controls

prolonged proestrus ( J:141251 )

♀ • at 2 months of age, many double homozygous females spend more than twice as much time in proestrus than wild-type controls

prolonged estrous cycle ( J:141251 )

♀ • at 2-, 4-, and 6 months of age, double homozygous females exhibit prolonged irregular estrous cycle lengths, averaging ~2 to 3 times longer than those of age-matched wild-type controls

endocrine/exocrine glands

small testis ( J:54681 )

♂

immune system

increased anti-double stranded DNA antibody level ( J:70420 )

cellular

increased apoptosis ( J:141251 )

• double homozygous females exhibit increased cell death in the nose and dorsal forebrain relative to wild-type controls

increased neuron apoptosis ( J:141251 )

• at E15, caspase 3 cleavage analysis revealed a 1.8-fold increase in the number of apoptotic cells in the dorsal forebrain, consistent with the location of loss of GnRH neurons number during migration

impaired neuronal migration ( J:141251 )

• at E15, double homozygous females show a 36% deficit in the appropriate targeting and positioning of GnRH neurons in the ventral forebrain

nervous system

increased neuron apoptosis ( J:141251 )

• at E15, caspase 3 cleavage analysis revealed a 1.8-fold increase in the number of apoptotic cells in the dorsal forebrain, consistent with the location of loss of GnRH neurons number during migration

impaired neuronal migration ( J:141251 )

• at E15, double homozygous females show a 36% deficit in the appropriate targeting and positioning of GnRH neurons in the ventral forebrain

abnormal forebrain morphology ( J:141251 )

• at 2 months of age, double homozygous females show a 24% decrease in the total number of gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus relative to wild-type controls

• a more striking deficit (34%) of GnRH neurons is noted in regions surrounding the organum vasculosum of the lamina terminalis (OVLT), known to be critical for the GnRH-induced LH surge

abnormal forebrain development ( J:141251 )

• at E15, double mutant brains show a striking loss (36%) of GnRH-immunoreactive cells within the context of ventral forebrain but not more rostrally