Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Former Names 129/Sv-Dhhtm1Amc/J    (Changed: 15-DEC-04 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Andrew McMahon,   Harvard University

Description
Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. Homozygous male mice are sterile due to arrested spermatogenesis at the late meiosis, primary spermatocyte stage. Female homozygotes are fertile. No gene product (mRNA) was detectable by semiquantitative RT-PCR analysis of peripheral nerve. Embryonic testis development is impaired. By six weeks of age, the mass of testes from homozygous males is 90% smaller than testes from heterozygous males. Histological examination reveals a diminished number of germ cells and no mature sperm in the testis or epididymis. Peripheral nerves from mutant mice appear flattened with structurally disorganized protective sheaths. The perineural cells, glia and mesenchymal cells, develop defective tight junctions, causing the perineurium to be permeable. This mutant mouse strain may be useful in studies related to male sterility and regulation of peripheral nerve development.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exons 1 and 2 and a portion of exon 3, which encode a conserved polypeptide required for protein activity. The construct was electroporated into 129S1/Sv-p⁺ Tyr⁺ Kitl^Sl-J/+ derived CJ7 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts.

Additional Web Information

New 129 Nomenclature Bulletin

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Gonadal Dysgenesis, 46,XY, Partial, with Minifascicular Neuropathy - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Dhh^tm1Amc/Dhh^tm1Amc

        involves: 129S1/Sv * C57BL/6J

• endocrine/exocrine gland phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:57914)
  • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells
  • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost
• abnormal Sertoli cell morphology (MGI Ref ID J:57914)
  • only a residual lining of Sertoli cells was observed in most males
• small testis (MGI Ref ID J:57914)
  • a progressive reduction in testicular mass was grossly evident at 18.5 dpc
• reproductive system phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:57914)
  • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells
  • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost
• abnormal Sertoli cell morphology (MGI Ref ID J:57914)
  • only a residual lining of Sertoli cells was observed in most males
• abnormal spermatogenesis (MGI Ref ID J:57914)
  • on a 129/Sv x C57BL/6J hybrid background, germ cells of some mice progressed through meiosis to late stages of spermiogenesis but sperm development was blocked at step 15; in contrast, on an inbred 129/Sv background, primary spermatocytes were formed but underwent cell death
• arrest of spermiogenesis (MGI Ref ID J:57914)
  • although step 15 spermatids were detected in tubules undergoing the transition from stage VI to stage VII, no step 16 spermatids were found in stage VII tubules, suggesting a developmental block at this stage
• azoospermia (MGI Ref ID J:57914)
  • no mature sperm were detected in the testis or epididymis
• male infertility (MGI Ref ID J:57914)
  • male homozygotes were viable and displayed normal male anatomy and behavior but were infertile
  • in contrast, female homozygotes were fully fertile
• small testis (MGI Ref ID J:57914)
  • a progressive reduction in testicular mass was grossly evident at 18.5 dpc

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Dhh^tm1Amc/Dhh^tm1Amc

        involves: 129S1/Sv

• endocrine/exocrine gland phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:57914)
  • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells
  • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost
• abnormal Sertoli cell morphology (MGI Ref ID J:57914)
  • only a residual lining of Sertoli cells was observed in most males
• small testis (MGI Ref ID J:57914)
  • at 18.5 dpc, homozygous mutant testes were grossly smaller than those of heterozygous littermates
  • a progressive reduction in testicular mass was observed amounting to a 60% decrease at P10 and a 90% decrease at 6 weeks of age
• reproductive system phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:57914)
  • in most males, the seminiferous tubules were largely devoid of germ cells and contained only a residual lining of Sertoli cells
  • notably, Leydig cells were present at 18.5 dpc but expression of patched homolog 1 was lost
• abnormal Sertoli cell morphology (MGI Ref ID J:57914)
  • only a residual lining of Sertoli cells was observed in most males
• abnormal spermatid morphology (MGI Ref ID J:57914)
  • spermatids were not observed
• arrest of spermatogenesis (MGI Ref ID J:57914)
  • on an inbred 129/Sv background, primary spermatocytes were formed but underwent cell death and no spermatids were observed; in contrast, on a 129/Sv x C57BL/6J hybrid background, germ cells of some mice progressed through meiosis to late stages of spermiprimary spermatocytes formed and underwent cell death ogenesis but sperm development was blocked at step 15
• azoospermia (MGI Ref ID J:57914)
  • no mature sperm were detected in the testis or epididymis
• male infertility (MGI Ref ID J:57914)
  • male homozygotes were viable and displayed normal male anatomy and behavior but were infertile
  • in contrast, female homozygotes were fully fertile
• small testis (MGI Ref ID J:57914)
  • at 18.5 dpc, homozygous mutant testes were grossly smaller than those of heterozygous littermates
  • a progressive reduction in testicular mass was observed amounting to a 60% decrease at P10 and a 90% decrease at 6 weeks of age

Dhh^tm1Amc/Dhh^tm1Amc

        involves: 129/Sv

• nervous system phenotype
• abnormal nervous system morphology (MGI Ref ID J:57341)
  • sciatic nerve flattened rather than round in cross-section
  • little collagen in epineurium
  • few fibroblasts in epineurium but perineurium-like cells present
  • 2-4 layers in perineurium as opposed to 6-8 layers normally
  • discontinuous basal lamina in perineurium
  • cell junction defects between perineurium cells
  • perineurial-like cells invade endoneurial space
  • defective nerve tissue barrier, granulocyte invasion of nerves in inflammation

Dhh^tm1Amc/Dhh^tm1Amc

        involves: 129S1/Sv * C57BL/6J * Swiss Webster

• endocrine/exocrine gland phenotype
• abnormal seminiferous tubule morphology (MGI Ref ID J:65900)
  • irregular and anastomotic tubules were observed in feminized adult males; tubular profiles were not rounded and the intertubular tissue displayed a few Leydig cells but extensive fibroblastic tissue
  • relatively normal tubule appearance in masculinized adult males with small Sertoli cells and abundant adult-type Leydig cells in the interstitial lymphatic space
• abnormal Leydig cell morphology (MGI Ref ID J:65900)
  • masculinized adult males exhibited adult-type Leydig cells characterized by a dense cytoplasmic matrix, abundant smooth endoplasmic reticulum (SER), whorled ER, and a relative scarcity of lipid and glycogen, as well as an incomplete layer of parietal lymphatic endothelial cells external to the myoid cell layer
  • in contrast, feminized males lacked both adult-type Leydig cells and a complete layer of parietal lymphatic endothelial cells; a few clusters of fetal-type Leydig cells were observed, with relatively less SER, a less dense cytoplasmic matrix compared to adult-type Leydig cells, no whorled SER, and abundant lipid and glycoge
• Leydig cell hyperplasia (MGI Ref ID J:65900)
  • abundance of adult-type Leydig cells in the interstitial lymphatic space of masculinized males
• Leydig cell hypoplasia (MGI Ref ID J:65900)
  • significant reduction or near absence of adult-type Leydig cells in the interstitial testicular region of feminized males
  • the relatively few Leydig cells that were present were identified as fetal based on their distinct morphology
• abnormal Sertoli cell morphology (MGI Ref ID J:65900)
  • in masculinized males, Sertoli cells were small and lacked a normal architecture in the relative absence of germ cells
  • in feminized males, absence of a basement membrane resulted in apolar Sertoli cells
• abnormal peritubular myoid cell morphology (MGI Ref ID J:65900)
  • feminized males displayed immature myoid cells that were abnormally thickened instead of being flattened and lacked organized actin filaments and the pinocytotic vesicles observed in control testes
  • in some cases, the myoid cell layer around the seminiferous tubules was discontinuous, with only collagen in the place of absent cells
  • in some regions of feminized testes, the basement membrane between the myoid cell and cells of the seminiferous tubules was absent, whereas in other regions, the myoid cells gave rise to numerous microvilli that impinged upon the Sertoli cells
• decreased number of peritubular myoid cells (MGI Ref ID J:65900)
  • at 20 days of age, no myoid cells or parietal lymphatic cells could be identified in feminized males
  • in some cases where the basement membrane was absent, there was a direct intermingling of Leydig cells with Sertoli cells without any intervening peritubular tissue or extracellular basal laminae
• abnormal testis cord formation (MGI Ref ID J:65900)
  • the basal lamina of seminiferous cords was not always continuous in newborn and adult mutant mice
• cryptorchism (MGI Ref ID J:65900)
  • mutant testes were embedded in the fat pads in proximity to the kidneys
• small testis (MGI Ref ID J:65900)
  • extremely reduced size of testes in both masculinized and feminized males
  • testes of masculinized males were larger than those of feminized males
• decreased testis weight (MGI Ref ID J:65900)
  • the mean paired testis weight of feminized males was reduced to only 5% of that in heterozygous control mice
• homeostasis/metabolism phenotype
• decreased circulating testosterone level (MGI Ref ID J:65900)
  • reduced levels of circulating testosterone in feminized males relative to controls (1.39 ± 0.05 ng/ml vs 3.6 ± 0.64 ng/ml, respectively)
• increased circulating luteinizing hormone level (MGI Ref ID J:65900)
  • increased levels of circulating LH in feminized males relative to controls (14.1 ± 2.5 ng/ml vs 4.9 ± 1.0 ng/ml, respectively)
  • normal serum levels of follicle stimulating hormone (FSH) in feminizied males relative to controls
• reproductive system phenotype
• abnormal anogenital distance (MGI Ref ID J:65900)
  • masculinized males displayed a relatively longer urogenital-anal distance than feminized males
• abnormal male germ cell morphology (MGI Ref ID J:65900)
  • in newborn (1-day-old) mice, germ cells were largely present within the seminiferous cords, but many were also found outside the cords
  • no synaptonemal complexes were noted in extracordal germ cells, indicating that meiotic development had not occurred
  • by 8 days of age, nearly all extracordal germ cells had been lost
• abnormal spermatocyte morphology (MGI Ref ID J:65900)
  • spermatogonia were evident but only a few spermatocytes were observed in masculinized adult males
  • rare spermatocytes were observed in feminized adult males
• abnormal spermatogonia morphology (MGI Ref ID J:65900)
  • rare spermatogonia were observed in feminized adult males
• abnormal seminiferous tubule morphology (MGI Ref ID J:65900)
  • irregular and anastomotic tubules were observed in feminized adult males; tubular profiles were not rounded and the intertubular tissue displayed a few Leydig cells but extensive fibroblastic tissue
  • relatively normal tubule appearance in masculinized adult males with small Sertoli cells and abundant adult-type Leydig cells in the interstitial lymphatic space
• abnormal Leydig cell morphology (MGI Ref ID J:65900)
  • masculinized adult males exhibited adult-type Leydig cells characterized by a dense cytoplasmic matrix, abundant smooth endoplasmic reticulum (SER), whorled ER, and a relative scarcity of lipid and glycogen, as well as an incomplete layer of parietal lymphatic endothelial cells external to the myoid cell layer
  • in contrast, feminized males lacked both adult-type Leydig cells and a complete layer of parietal lymphatic endothelial cells; a few clusters of fetal-type Leydig cells were observed, with relatively less SER, a less dense cytoplasmic matrix compared to adult-type Leydig cells, no whorled SER, and abundant lipid and glycoge
• Leydig cell hyperplasia (MGI Ref ID J:65900)
  • abundance of adult-type Leydig cells in the interstitial lymphatic space of masculinized males
• Leydig cell hypoplasia (MGI Ref ID J:65900)
  • significant reduction or near absence of adult-type Leydig cells in the interstitial testicular region of feminized males
  • the relatively few Leydig cells that were present were identified as fetal based on their distinct morphology
• abnormal Sertoli cell morphology (MGI Ref ID J:65900)
  • in masculinized males, Sertoli cells were small and lacked a normal architecture in the relative absence of germ cells
  • in feminized males, absence of a basement membrane resulted in apolar Sertoli cells
• abnormal peritubular myoid cell morphology (MGI Ref ID J:65900)
  • feminized males displayed immature myoid cells that were abnormally thickened instead of being flattened and lacked organized actin filaments and the pinocytotic vesicles observed in control testes
  • in some cases, the myoid cell layer around the seminiferous tubules was discontinuous, with only collagen in the place of absent cells
  • in some regions of feminized testes, the basement membrane between the myoid cell and cells of the seminiferous tubules was absent, whereas in other regions, the myoid cells gave rise to numerous microvilli that impinged upon the Sertoli cells
• decreased number of peritubular myoid cells (MGI Ref ID J:65900)
  • at 20 days of age, no myoid cells or parietal lymphatic cells could be identified in feminized males
  • in some cases where the basement membrane was absent, there was a direct intermingling of Leydig cells with Sertoli cells without any intervening peritubular tissue or extracellular basal laminae
• abnormal spermatogenesis (MGI Ref ID J:65900)
  • both masculinized (7.5%) and feminized (92.5%) males showed abnormal peritubular tissue and severely depressed spermatogenesis
• abnormal spermatocyte morphology (MGI Ref ID J:65900)
  • spermatogonia were evident but only a few spermatocytes were observed in masculinized adult males
  • rare spermatocytes were observed in feminized adult males
• abnormal testis cord formation (MGI Ref ID J:65900)
  • the basal lamina of seminiferous cords was not always continuous in newborn and adult mutant mice
• cryptorchism (MGI Ref ID J:65900)
  • mutant testes were embedded in the fat pads in proximity to the kidneys
• male infertility (MGI Ref ID J:65900)
• male pseudohermaphroditism (MGI Ref ID J:65900)
  • 92.5% of mutant males were pseudohermaphrodites with an external female phenotype, evidence of mammary teats, and a blind vaginal opening; the remaining 7.5% mutant males were masculinized
  • penetrance within the 92.5% varied; for example, some males were only partly feminized with colored teat hairs but lacking a blind vaginal opening
  • internally, masculinized males were similar to feminized males except that the overall size of the reproductive tract was relatively larger, although still smaller, than that of wild-type or heterozygous controls
• small testis (MGI Ref ID J:65900)
  • extremely reduced size of testes in both masculinized and feminized males
  • testes of masculinized males were larger than those of feminized males
• decreased testis weight (MGI Ref ID J:65900)
  • the mean paired testis weight of feminized males was reduced to only 5% of that in heterozygous control mice
• digestive/alimentary phenotype
• abnormal anogenital distance (MGI Ref ID J:65900)
  • masculinized males displayed a relatively longer urogenital-anal distance than feminized males
• other phenotype
• fibrosis (MGI Ref ID J:65900)
  • feminized males show numerous layers of fibroblast-like cells with abundant intervening collagen external to the seminiferous tubules
  • the fibrosis produced by the accumulation of collagen fibers in the interstitium of feminized testes increased with age

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Dhh^tm1Amc related

Developmental Biology Research
Internal/Organ Defects (gonads)
Neurodevelopmental Defects

Neurobiology Research
Neurodevelopmental Defects

Reproductive Biology Research
Fertility Defects (males only)

Genes & Alleles

Gene & Allele Information

Allele Symbol		Dhhtm1Amc
Allele Name		targeted mutation 1, Andrew P McMahon
Allele Type		Targeted (knock-out)
Common Name(s)		Dhh-;
Mutation Made By		Andrew McMahon,   Harvard University
Strain of Origin		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
ES Cell Line Name		CJ7
ES Cell Line Strain		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Gene Symbol and Name		Dhh, desert hedgehog
Chromosome		15
Gene Common Name(s)		C78960; HHG-3; MGC35145; expressed sequence C78960;
Molecular Note		Exons 1, 2 and part of 3 were replaced with a neomycin cassette. The deleted segments encode a conserved polypeptide required for protein function. Thus, no functional protein is predicted to be produced from this allele. [MGI Ref ID J:57914]

Genotyping

Genotyping Information

Genotyping Protocols

Dhh^tm1Amc, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Bitgood MJ; Shen L; McMahon AP. 1996. Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol 6(3):298-304. [PubMed: 8805249]  [MGI Ref ID J:57914]

Additional References

Parmantier E; Lynn B; Lawson D; Turmaine M; Namini SS; Chakrabarti L; McMahon AP; Jessen KR; Mirsky R. 1999. Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths [see comments] Neuron 23(4):713-24. [PubMed: 10482238]  [MGI Ref ID J:57341]

Dhh^tm1Amc related

Brennan J; Capel B. 2004. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet 5(7):509-21. [PubMed: 15211353]  [MGI Ref ID J:90770]

Clark AM; Garland KK; Russell LD. 2000. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type leydig cells and normal development of peritubular cells and seminiferous tubules Biol Reprod 63(6):1825-38. [PubMed: 11090455]  [MGI Ref ID J:65900]

Mirsky R; Parmantier E; McMahon AP; Jessen KR. 1999. Schwann cell-derived desert hedgehog signals nerve sheath formation. Ann N Y Acad Sci 883:196-202. [PubMed: 10586245]  [MGI Ref ID J:59851]

Park SY; Tong M; Jameson JL. 2007. Distinct roles for steroidogenic factor 1 and desert hedgehog pathways in fetal and adult Leydig cell development. Endocrinology 148(8):3704-10. [PubMed: 17495005]  [MGI Ref ID J:129625]

Parmantier E; Lynn B; Lawson D; Turmaine M; Namini SS; Chakrabarti L; McMahon AP; Jessen KR; Mirsky R. 1999. Schwann cell-derived Desert hedgehog controls the development of peripheral nerve sheaths [see comments] Neuron 23(4):713-24. [PubMed: 10482238]  [MGI Ref ID J:57341]

Pierucci-Alves F; Clark AM; Russell LD. 2001. A developmental study of the Desert hedgehog-null mouse testis. Biol Reprod 65(5):1392-402. [PubMed: 11673255]  [MGI Ref ID J:108687]

Sharghi-Namini S; Turmaine M; Meier C; Sahni V; Umehara F; Jessen KR; Mirsky R. 2006. The structural and functional integrity of peripheral nerves depends on the glial-derived signal desert hedgehog. J Neurosci 26(23):6364-76. [PubMed: 16763045]  [MGI Ref ID J:109214]

Umehara F; Mishima K; Egashira N; Ogata A; Iwasaki K; Fujiwara M. 2006. Elevated anxiety-like and depressive behavior in Desert hedgehog knockout male mice. Behav Brain Res 174(1):167-73. [PubMed: 16952407]  [MGI Ref ID J:112866]

Yao HH; Whoriskey W; Capel B. 2002. Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev 16(11):1433-40. [PubMed: 12050120]  [MGI Ref ID J:82007]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	The resulting mice were crossed at least once to C57BL/6, and have been maintained on a 129 background. The Donating Investigator maintains the strain by crossing homozygous females with heterozygous males. Homozygous males are sterile.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. At least two mice that carry the mutation (if it is a mutant strain) will be provided. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotypes and genders are needed. IMPORTANT NOTE: The genotypes of the animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire for possible genotypes for this specific strain. Animals typically ship within 13 to 16 weeks from your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will typically ship within 25 weeks. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
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JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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