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Mouse Pathology Spontaneous Phenotypes and Diseases (NON 2017 Brayton MICE NON infectious 32p OPC Disclosures Mouse Pathology No financial disclosures that I know of… Spontaneous Phenotypes All opinions expressed and implied in and Diseases (NON infectious) this presentation are solely those of Dr. Brayton. The content of the presentation does Cory Brayton, DVM, DipACLAM, DipACVP not represent or reflect the views of Associate Professor, Molecular and Comparative Pathobiology Director, Phenotyping Core Johns Hopkins University or Johns Johns Hopkins University, School of Medicine Hopkins Health system. Baltimore, MD 21205 [email protected] http://www.hopkinsmedicine.org/mcp/PHENOCORE/index.html 3 General References Resources online 1. ACLAM Blue books https://www.elsevier.com/books/book‐series/american‐college‐of‐ laboratory‐animal‐medicine 1. Brayton: Spontaneous diseases in commonly used mouse strains and stocks (2013) http://phenome.jax.org/projects/Brayton1 – The Mouse in Biomedical Research. Fox, Barthold, Davisson et al. Vol I‐IV 2006 – Lab manual at http://www.hopkinsmedicine.org/mcp/PHENOCORE/courseCURRENT.html – Laboratory Animal Medicine Fox et al 2015 2. DORA Diseases of Research Animals http://dora.missouri.edu/ 2. Barthold S, Griffey S, Percy D. 2016. Pathology of Laboratory Rodents and Rabbits, Wiley‐ Blackwell. 3. Frith and Ward. 1988. A Color Atlas of Neoplastic and Non Neoplastic Lesions in Aging Mice. http://www.informatics.jax.org/frithbook/ also print on Demand from 3. Brayton C. 2006. Spontaneous Diseases in Commonly Used Mouse Strains The Mouse in http://store.cldavis.org/ Biomedical Research. Fox, Barthold, Davisson et al. New York, Elsevier (Academic Press). II. Diseases: 623‐717. outline at http://phenome.jax.org/projects/Brayton1 4. MGI Mouse Genome Informatics SEARCH GENES etc info http://www.informatics.jax.org/ 4. Brayton C, Treuting P, Ward J. 2012. Pathobiology of aging mice and GEM: background – IMSR ‐ FIND MICE AND ES CELL LINES http://www.findmice.org/index.jsp strains and experimental design. Vet Pathol. 49(1):85‐105. – Mouse (rat) and Gene NOMENCLATURE & apply for a laboratory code 5. Treuting P and Dintzis S, Eds. 2012. Comparative Anatomy and Histology: A Mouse and http://www.informatics.jax.org/mgihome/nomen/index.shtml Human Atlas. Elsevier (Academic Press): London. pp. 361‐381. – MPD‐ Mouse Phenome Database mouse data and protocols http://phenome.jax.org/ new edition in press 2017 –with RATS – MTB Database & tumor frequency grid http://tumor.informatics.jax.org/mtbwi/index.do Primary Journals 5. Noah’s Arkive (now at CLDavis) http://noahsarkive.cldavis.org/ 1. Comparative medicine / JAALAS (Search Comp Med, JAALAS) 6. NTP NON neoplastic lesion atlas http://ntp.niehs.nih.gov/nnl/ 2. Journal of Comparative Pathology (search J Comp Pathol) 7. Pathbase: European mutant mouse pathology database http://www.pathbase.net/ 3. [Laboratory animals (Sage); Lab An (NY) (Nature.com)] 8. RENI Tissue trimming guide + INHAND terminology and diagnostic criteria 4. Toxicologic Pathology (search toxicol pathol) http://www.goreni.org/ 5. Veterinary Pathology (search vet pathol) 9. VSPO JPC https://www.askjpc.org/vspo/ Etc. spontaneous conditions in Some Phenotypes (& Pathology) of recent literature: PubMed SEARCH ‘Normal’ mice (short list) vet pathol [jo] YEAR mice Comp med [jo] YEAR mice C57BL/6? Microphthalmia, hydrocephalus, ulcerative dermatitis, osteoporosis, presbyacusis, AMP, amyloidosis, vet pathol [jo] YEAR rats Comp med [jo] YEAR rats lymphoma, histiocytic sarcoma .… 129? Teratomas (Ter), lung tumors, AMP, hyalinosis, acallosity, megaesophagus, otitis, lymphoma … toxicol pathol [jo] YEAR mice jaalas [jo] YEAR mice FVB? rd1, seizures, lung tumors, AMP, mammary/ pituitary dz …. toxicol pathol [jo] YEAR rats jaalas [jo] YEAR rats j comp path [jo] YEAR mice lab anim [jo] YEAR mice DEAF‐ C57BL/6, BALB, DBA, etc BLIND dt rd1 ‐ C3H, CBA, SJL, SWR, FVB j comp path [jo] YEAR rats lab anim [jo] YEAR rats C5 deficient 9 [email protected] 2017 Page 1 of 32 2017 Brayton MICE NON infectious 32p Phenotypes to expect When to expect them Discussion Plan Malocclusion Younger mice Important Phenotypes Hydrocephalus (By weaning) 1. Sexual dimorphisms. Sexual dimorphisms Blind / Deaf 2. 2 killers to identify at/by weaning. SKIN/HAIR: Barbering / dermatitis Various ages 3. 3 Common clinical complaints. Imperforate vagina MUS Hydronephrosis 4. 4 Sick old mouse phenotypes. Vestibular syndromes 5. Top 5 tumors Acidophilic Macrophage pneumonia AIM: DON’T LET THESE MESS UP YOUR RESEARCH Amyloidosis & glomerulonephritis Older mice Arteritis 6. A few more fun findings …. Tumors13 14 1. Some Sexual Dimorphisms SEX MATTERS Prevalence of sexual dimorphism in mammalian Size growth curves = NICE DATA ! phenotypic traits. Are the GEM really smaller? Slower growing ? – Nat Commun. 2017 Jun 26;8:15475. Anogenital distance –tough in younger https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490203/ . In utero influences – How many authors does it take to convince a scientist? Nipples –not in males Karp et al: Mason J, Beaudet AL, Benjamini Y, Bower L, Braun RE, Brown SDM, Chesler EJ, Dickinson ME, Flenniken AM, Fuchs H, Angelis MH, Gao X, Guo S, Greenaway S, Heller R, Herault Y, Justice MJ, Kurbatova N, Lelliott CJ, Lloyd KCK, Mallon AM, Mank JE, Masuya H, Salivary glands – bigger in males McKerlie C, Meehan TF, Mott RF, Murray SA, Parkinson H, Ramirez‐Solis R, Santos L, Seavitt JR, Smedley D, Sorg T, Speak AO, Steel KP, Svenson KL; International Mouse Phenotyping Consortium, Wakana S, West D, Wells S, Westerberg H, Yaacoby S, White JK. +159 . Acidophilic tubules Collaborators: bata Y, Suzuki T, Tamura M, Kaneda H, Furuse T, Kobayashi K, Miura I, Yamada I, Tanaka N, Yoshiki A, Ayabe S, Clary DA, Tolentino HA, Schuchbauer MA, Tolentino T, Aprile JA, Pedroia SM, Kelsey L, Vukobradovic I, Berberovic Z, Owen C, Qu D, Guo R, Kidneys – bigger in females ? Males ? Newbigging S, Morikawa L, Law N, Shang X, Feugas P, Wang Y, Eskandarian M, Zhu Y, Nutter LMJ, Penton V,P, Laurin Clarke S, Lan Q, Sohel K, Miller D, Clark G, Hunter J, Cabezas J, Bubshait M, Carroll T, Tondat S, MacMaster S, Pereira M, Gertsenstein M, Danisment O, Jacob E, Creighton A, Sleep G, Clark J, Teboul L, Fray M, Caulder A, Loeffler J, Codner G, Cleak J, Johnson S, Szoke‐Kovacs Z, Radage A, Maritati M, Mianne J, Gardiner . Cuboidal parietal epithelium –male (>> female) W, Allen S, Cater H, Stewart M, Keskivali‐Bond P, Sinclair C, Brown E, Doe B, Wardle‐Jones H, Grau E, Griggs N, Woods M, Kundi H, Griffiths MND, Kipp C, Melvin DG, Raj NPS, Holroyd SA, Gannon DJ, Alcantara R, Galli A, Hooks YE, Tudor CL, Green AL, Kussy FL, Tuck EJ, Siragher EJ, Maguire SA, Lafont DT, Vancollie VE, Pearson SA, Gates AS, Sanderson M, Shannon C, Anthony LFE, Sumowski MT, McLaren RSB, Swiatkowska A, Adrenal glands – bigger in females Isherwood CM, Cambridge EL, Wilson HM, Caetano SS, Mazzeo CI, Dabrowska MH, Lillistone C, Estabel J, Maguire AKB, Roberson LA, Pavlovic G, Birling MC, Marie WD, Jacquot S, Ayadi A, Ali‐Hadji D, Charles P, André P, Le Marchand E, El Amri A, Vasseur L, Aguilar‐Pimentel A, Becker L, Treise I, Moreth K, Stoeger T, Amarie OV, Neff F, Wurst W, Bekeredjian R, Ollert M, Klopstock T, Calzada‐Wack J, Marschall S, Brommage R, . X zone (vacuolar change in females) 16 Steinkamp R, Lengger C, Östereicher MA, Maier H, Stoeger C, Leuchtenberger S, Yildrim A, Garrett L, Hölter SM, Zimprich A, Seisenberger C, 15 Bürger A, Graw J, Eickelberg O, Zimmer A, Wolf E, Busch DH, Klingenspor M, Schmidt‐Weber C, Gailus‐Durner V, Beckers J, Rathkolb B, Rozman J. Sex and SIZE 1. Some Sexual Dimorphisms (+ Genetic Background) ♂ If they’re normal, SIZE (body weight) what’s the big deal? Cheapest Data you can get? M > F – B6D2F1 ~ Hi? Are there sexual dimorphisms in the data, or – C3H/HeJ ~ lo research endpoints ? Jax Phenome Database ANALYZE Male & Female data separately data by strain sex age protocol – Jax Pheno1 ♀ ALSO CONSIDER: NOT having these may be – n = 5‐15 an important phenotype – 6% fat diet NIH 316 Purina 5K52 17 18 [email protected] 2017 Page 2 of 32 2017 Brayton MICE NON infectious 32p Sexing pups Salivary Glands, associated Nodes Nice pictures at http://www.thefunmouse.com/info/sexing.cfm Which is Male ? A A or B ? 1. Submandibular 2. Sublingual B 3. Parotid (exorbital lacrimal) 4. Lymph nodes Nipples may be evident by about 6do 21 Tissues? Tissue? Which is Male? Which is more likely to be male? AB AB 22 23 Tissue? Which is Female ? 1. Sexual Dimorphisms ABFEMALE Size Growth Curves = NICE DATA ! Salivary glands, Kidneys, Adrenal glands etc Many More CONCLUSIONS: EXPECT THE EXPECTED – consider the unexpected ANALYZE Male & Female data separately 24 25 Missing Dimorphisms may be a phenotype [email protected] 2017 Page 3 of 32 2017 Brayton MICE NON infectious 32p 2. 2 Young Mouse Phenotypes Hydrocephalus to identify by / at weaning: Especially C57BL 1. Hydrocephalus . Later onset not evident at weaning E.g. sporadic in MRL etc. 2. Malocclusion / Incisor overgrowth . Cull or trim . Breed?? 3. Microphthalmia . Expect this in C57BL –but it won’t kill them 26 . Especially? Right eye in females 27 Malocclusion , incisor overgrowth 2. 2 Young Mouse Phenotypes Secondary Phenotypes to identify by / at weaning: 1. Hydrocephalus 2. Malocclusion / Incisor overgrowth 3. Microphthalmia etc dysmorphisms 6g –6 weeks old CONCLUSIONS: ‘Developmental delay’ EXPECT THE EXPECTED – consider the unexpected – important phenotype? or just not eating (inanition)? DON’T let these kill your mice ! Examine your mice ! 28Early Death 29 i i d i ih h Pup assessments p0 Eyes closed Open ~p14 Ears closed Open ~p3‐5 MILK spot By 6hr… Not evident (externally) by approx p6 NO FUR Fuzz starts ~p2‐6 NO incisors Erupting ~p11 Nibbling solid food ~p12 NO nipples females ~p9 Males should NOT have them • RECORD/REPORT: Weight Milk spot (food in stomach in older pups) When little or no milk is present by 6 hours after birth, it is almost certainly the case that something is wrong with either the pup or the mother.
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