Phenotypes associated with this allele

• Allele Symbol: Huwe1^tm1Alas
• Allele Name: targeted mutation 1, Anna Lasorella
• Allele ID: MGI:4439480
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Huwe1^tm1Alas/Y Tg(Prm-cre)58Og/0	involves: 129S4/SvJae * 129S7/SvEvBrd	MGI:7286185
cn2	Huwe1^tm1Alas/Y Tg(Nes-cre)1Kag/0	involves: 129S7/SvEvBrd	MGI:4821353
cn3	Huwe1^tm1Alas/Y Tg(Spo11-cre)1Rsw/0	involves: 129S7/SvEvBrd	MGI:7286184
cn4	Huwe1^tm1Alas/Y Tg(Stra8-icre)1Reb/0	involves: 129S7/SvEvBrd * C57BL/6 * FVB/NJ	MGI:7286183

Genotype
MGI:7286185

cn1

• Allelic Composition: Huwe1^tm1Alas/Y; Tg(Prm-cre)58Og/0
• Genetic Background: involves: 129S4/SvJae * 129S7/SvEvBrd

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

reproductive system

reproductive system phenotype ( J:323709 )

♂N • male mice are fertile and show normal spermatogenesis with no significant differences in sperm number, sperm motility or testis weights relative to control males

Genotype
MGI:4821353

cn2

• Allelic Composition: Huwe1^tm1Alas/Y; Tg(Nes-cre)1Kag/0
• Genetic Background: involves: 129S7/SvEvBrd

mortality/aging

neonatal lethality ( J:152966 )

♂

nervous system

abnormal neuronal precursor proliferation ( J:152966 )

♂ • at E18.5, the length of the cycle is lengthened compared to in wild-type cells

♂ • at E13.5, E15.5, E18.5, fewer progenitors exit the cell cycle compared with wild-type mice

♂ • at E18.5, proliferation of neuronal precursors is increased compared to in wild-type mice

abnormal brain morphology ( J:152966 )

♂ • brains contain ectopic cellular clusters in differentiated striatal regions unlike in wild-type mice

♂ • however, no abnormalities are observed at E15.5

decreased brain size ( J:152966 )

♂

abnormal dentate gyrus morphology ( J:152966 )

♂ • poorly developed

abnormal cerebral cortex morphology ( J:152966 )

♂ • the cortex exhibits an increase in cellular density and decrease in intervening neuropil compared to in wild-type mice

abnormal stratification in cerebral cortex ( J:152966 )

♂ • laminar organization is altered with no clearly identifiable superficial neuron layers compared to in wild-type mice

thin cerebral cortex ( J:152966 )

♂

small cerebellum ( J:152966 )

♂ • very small

increased neuronal precursor cell number ( J:152966 )

♂ • in the germinal layers

cellular

abnormal neuronal precursor proliferation ( J:152966 )

♂ • at E13.5, E15.5, E18.5, fewer progenitors exit the cell cycle compared with wild-type mice

♂ • at E18.5, proliferation of neuronal precursors is increased compared to in wild-type mice

♂ • at E18.5, the length of the cycle is lengthened compared to in wild-type cells

Genotype
MGI:7286184

cn3

• Allelic Composition: Huwe1^tm1Alas/Y; Tg(Spo11-cre)1Rsw/0
• Genetic Background: involves: 129S7/SvEvBrd

reproductive system

reproductive system phenotype ( J:323709 )

♂N • male mice are fertile and show no apparent defects in spermatogenesis, epididymal sperm number, sperm motility or meiotic progression relative to control males

abnormal spermatocyte morphology ( J:323709 )

♂ • chromosome spreads prepared from 28dpp testes show a significantly higher % of spermatocytes that retain gammaH2AX on the autosomes in pachytene and diplotene spermatocytes (where normally gammaH2AX is found only on the XY body)

♂ • however, no significant increase in apoptosis is observed, as determined by a TUNEL assay

cellular

abnormal spermatocyte morphology ( J:323709 )

♂ • chromosome spreads prepared from 28dpp testes show a significantly higher % of spermatocytes that retain gammaH2AX on the autosomes in pachytene and diplotene spermatocytes (where normally gammaH2AX is found only on the XY body)

♂ • however, no significant increase in apoptosis is observed, as determined by a TUNEL assay

Genotype
MGI:7286183

cn4

• Allelic Composition: Huwe1^tm1Alas/Y; Tg(Stra8-icre)1Reb/0
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6 * FVB/NJ

reproductive system

abnormal spermatocyte morphology ( J:323709 )

♂ • at 48 days post retinoic acid injection (48dpRA), synchronized adult testes contain fewer Stra8+ pre-leptotene spermatocytes (located away from the basement membrane of the tubules), indicating a defect in spermatogonial differentiation

♂ • at 8 days post retinoic acid injection (8dpRA), synchronized testes show clear loss of pre-leptotene/leptotene spermatocytes (germ cells located away from the basement membrane) in the tubules

♂ • at 8dpRA, the average number of Stra8+ pre-leptotene spermatocytes is significantly reduced in synchronized testes, whereas the number of Stra8+ spermatogonia (located adjacent to the basement membrane) is normal

♂ • staining with SYCP3 (a marker used to identify different types of spermatocytes in meiotic prophase I) confirmed the presence of fewer leptotene spermatocytes at 8dpRA

♂ • at 10 days post-partum (dpp), unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci

abnormal spermatogonia morphology ( J:323709 )

♂ • at 48dpRA, spermatogonia differentiation is disrupted in synchronized adult testes, leading to formation of fewer pre-leptotene spermatocytes

♂ • at 48dpRA, expression of markers for differentiating spermatogonia (Stra8, Dazl, Sohlh2) is markedly reduced in synchronized adult testes

♂ • at 10 dpp, unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci

decreased male germ cell number ( J:323709 )

♂ • significant loss of differentiating spermatogonia, spermatocytes and extensive loss of spermatids are observed in the tubules at 4 months of age

oligozoospermia ( J:323709 )

♂ • average cauda epididymal sperm number is only 3% of that in control males

abnormal male meiosis ( J:323709 )

♂ • at 8dpRA, the proportion of proliferating Stra8+ pre-leptotene spermatocytes is reduced by ~50% while expression of early meiotic markers (Spo11, Smc1b, Sycp1, Sycp3) is significantly decreased in synchronized testes, indicating impaired entry into meiosis

increased testis apoptosis ( J:323709 )

♂ • at 8dpRA, synchronized testes show a significantly higher % of TUNEL+ tubules than control testes; similar results are obtained by staining the same sections with cleaved, activated caspase 3

abnormal male germ cell physiology ( J:323709 )

♂ • at 8dpRA, the proportion of proliferating Stra8+ pre-leptotene spermatocytes incorporating BrdU in synchronized testes is ~50% lower than in control testes

♂ • however, no difference is noted in the proportion of proliferating Stra8+ A1 spermatogonia at 8dpRA

increased male germ cell apoptosis ( J:323709 )

♂ • at 10 dpp, unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci, along with recruitment of pCHK2 to these gammaH2AX foci, indicating activation of the DNA damage response pathway

♂ • at 8dpRA, double staining for Tra98 (a germ cell marker) and cleaved caspase 3 showed a significant increase in male germ cell apoptosis in synchronized testes relative to control testes (~68% versus 46%, respectively)

♂ • no significant colocalization of p53 with gammaH2AX foci is observed, suggesting p53-independent apoptosis

small testis ( J:323709 )

♂ • adult males have significantly smaller testes than control males

decreased testis weight ( J:323709 )

♂ • average weight of adult testes is only 30% of control males

arrest of spermatogenesis ( J:323709 )

♂ • at 4 months of age, males show significant loss of differentiating spermatogonia, spermatocytes and extensive loss of spermatids in the seminiferous tubules, indicating a developmental arrest early in spermatogenesis

abnormal caput epididymis morphology ( J:323709 )

♂ • few sperm are present in the caput epididymis

male infertility ( J:323709 )

♂ • males fail to sire any litters during a 4-week fertility assay

♂ • however, the frequency of vaginal plugging is normal

cellular

abnormal spermatocyte morphology ( J:323709 )

♂ • at 48 days post retinoic acid injection (48dpRA), synchronized adult testes contain fewer Stra8+ pre-leptotene spermatocytes (located away from the basement membrane of the tubules), indicating a defect in spermatogonial differentiation

♂ • at 8 days post retinoic acid injection (8dpRA), synchronized testes show clear loss of pre-leptotene/leptotene spermatocytes (germ cells located away from the basement membrane) in the tubules

♂ • at 8dpRA, the average number of Stra8+ pre-leptotene spermatocytes is significantly reduced in synchronized testes, whereas the number of Stra8+ spermatogonia (located adjacent to the basement membrane) is normal

♂ • staining with SYCP3 (a marker used to identify different types of spermatocytes in meiotic prophase I) confirmed the presence of fewer leptotene spermatocytes at 8dpRA

♂ • at 10 days post-partum (dpp), unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci

abnormal spermatogonia morphology ( J:323709 )

♂ • at 48dpRA, spermatogonia differentiation is disrupted in synchronized adult testes, leading to formation of fewer pre-leptotene spermatocytes

♂ • at 48dpRA, expression of markers for differentiating spermatogonia (Stra8, Dazl, Sohlh2) is markedly reduced in synchronized adult testes

♂ • at 10 dpp, unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci

decreased male germ cell number ( J:323709 )

♂ • significant loss of differentiating spermatogonia, spermatocytes and extensive loss of spermatids are observed in the tubules at 4 months of age

oligozoospermia ( J:323709 )

♂ • average cauda epididymal sperm number is only 3% of that in control males

abnormal male meiosis ( J:323709 )

♂ • at 8dpRA, the proportion of proliferating Stra8+ pre-leptotene spermatocytes is reduced by ~50% while expression of early meiotic markers (Spo11, Smc1b, Sycp1, Sycp3) is significantly decreased in synchronized testes, indicating impaired entry into meiosis

increased testis apoptosis ( J:323709 )

♂ • at 8dpRA, synchronized testes show a significantly higher % of TUNEL+ tubules than control testes; similar results are obtained by staining the same sections with cleaved, activated caspase 3

abnormal male germ cell physiology ( J:323709 )

♂ • at 8dpRA, the proportion of proliferating Stra8+ pre-leptotene spermatocytes incorporating BrdU in synchronized testes is ~50% lower than in control testes

♂ • however, no difference is noted in the proportion of proliferating Stra8+ A1 spermatogonia at 8dpRA

increased male germ cell apoptosis ( J:323709 )

♂ • at 10 dpp, unsynchronized testes show an increased proportion of Stra8+ differentiating spermatogonia/pre-leptotene spermatocytes with intense gammaH2AX foci, along with recruitment of pCHK2 to these gammaH2AX foci, indicating activation of the DNA damage response pathway

♂ • at 8dpRA, double staining for Tra98 (a germ cell marker) and cleaved caspase 3 showed a significant increase in male germ cell apoptosis in synchronized testes relative to control testes (~68% versus 46%, respectively)

♂ • no significant colocalization of p53 with gammaH2AX foci is observed, suggesting p53-independent apoptosis

endocrine/exocrine glands

increased testis apoptosis ( J:323709 )

♂ • at 8dpRA, synchronized testes show a significantly higher % of TUNEL+ tubules than control testes; similar results are obtained by staining the same sections with cleaved, activated caspase 3

small testis ( J:323709 )

♂ • adult males have significantly smaller testes than control males

decreased testis weight ( J:323709 )

♂ • average weight of adult testes is only 30% of control males