Phenotypes associated with this allele

• Allele Symbol: Hmgcs2^tm1.1Yil
• Allele Name: targeted mutation 1.1, Omer YIlmaz
• Allele ID: MGI:6457108
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil Lgr5^tm1(cre/ERT2)Cle/Lgr5^+	involves: 129P2/OlaHsd * C3H * C57BL/6 * C57BL/6J	MGI:8159407
cn2	Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil Lgr5^tm3(cre/ERT2)Cle/Lgr5^+ Gt(ROSA)26Sor^tm9(CAG-tdTomato)Hze/Gt(ROSA)26Sor^+	involves: 129S6/SvEvTac * C3H * C57BL/6J * C57BL/6NCrl	MGI:8159410
cn3	Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil Tg(Vil1-cre/ERT2)23Syr/0	involves: C3H * C57BL/6 * C57BL/6J * DBA/2	MGI:8159406

Genotype
MGI:8159407

cn1

• Allelic Composition: Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil; Lgr5^{tm1(cre/ERT2)Cle}/Lgr5⁺
• Genetic Background: involves: 129P2/OlaHsd * C3H * C57BL/6 * C57BL/6J

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

digestive/alimentary system

abnormal intestinal crypt stem cell physiology ( J:280699 )

• when co-cultured with wild-type Paneth cells, flow-sorted GFP^hi intestinal stem cells (ISCs) from tamoxifen (TAM)-treated mice form 42.9% fewer and 34.6% smaller organoids than wild-type ISCs, indicating reduced organoid-initiating capacity

decreased intestinal crypt stem cell number ( J:280699 )

• when adult mice are treated with TAM for 20 days, the % of Lgr5-GFP^hi ISCs in small intestinal crypts is reduced by 50% at 1 day after the last TAM injection

abnormal small intestine crypts of Lieberkuhn morphology ( J:280699 )

• when adult mice are treated with TAM for 20 days, the frequencies of Lgr5-GFP^hi ISCs and Lgr5-GFP^low progenitors in small intestinal crypts are reduced by 50% at 1 day after the last TAM injection

endocrine/exocrine glands

decreased intestinal crypt stem cell number ( J:280699 )

• when adult mice are treated with TAM for 20 days, the % of Lgr5-GFP^hi ISCs in small intestinal crypts is reduced by 50% at 1 day after the last TAM injection

abnormal small intestine crypts of Lieberkuhn morphology ( J:280699 )

• when adult mice are treated with TAM for 20 days, the frequencies of Lgr5-GFP^hi ISCs and Lgr5-GFP^low progenitors in small intestinal crypts are reduced by 50% at 1 day after the last TAM injection

cellular

abnormal intestinal crypt stem cell physiology ( J:280699 )

• when co-cultured with wild-type Paneth cells, flow-sorted GFP^hi intestinal stem cells (ISCs) from tamoxifen (TAM)-treated mice form 42.9% fewer and 34.6% smaller organoids than wild-type ISCs, indicating reduced organoid-initiating capacity

Genotype
MGI:8159410

cn2

• Allelic Composition: Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil; Lgr5^{tm3(cre/ERT2)Cle}/Lgr5⁺; Gt(ROSA)26Sor^{tm9(CAG-tdTomato)Hze}/Gt(ROSA)26Sor⁺
• Genetic Background: involves: 129S6/SvEvTac * C3H * C57BL/6J * C57BL/6NCrl

digestive/alimentary system

abnormal jejunal goblet cell morphology ( J:280699 )

• 12 days after a single TAM injection, mice show a significant increase in the number of mucin+ goblet cells in proximal jejunal crypts

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of AB/PAS+ goblet cells in proximal jejunal crypts

abnormal intestinal crypt stem cell physiology ( J:280699 )

• when mice are treated with TAM 24 h prior to crypt isolation, ISCs cultured in standard medium are 34.4% less capable of forming organoids, with resulting organoids showing a 40.5% increase in goblet cells and a 64.3% decrease in tdTomato+ cells per organoid relative to controls

• exogenous beta-hydroxybutyrate (beta-OHB), but not lactate (a Paneth niche-derived metabolite that sustains ISC function), restores the organoid-forming capacity and generation of tdTomato + clones and rescues the secretory lineage bias

increased Paneth cell number ( J:280699 )

• 12 and >22 days after a single TAM injection, mice show a significant increase in the number of LYZ1+ Paneth cells in proximal jejunal crypts

• 5 days after a single TAM injection, flow-sorted Lgr5+ ISC-derived tdTomato+ progeny show a 5.8-fold increase in Paneth cells (7.88% vs 1.36% in controls)

• as early 24 h after TAM injection, ISCs generate significantly greater numbers of tdTomato+ Paneth cells in jejunal sections

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of LYZ+ Paneth cells in proximal jejunal crypts

abnormal jejunum crypts of Lieberkuhn morphology ( J:280699 )

• TAM-treated mice show a progressive loss of OLFM4+ intestinal stem cells (ISCs) and early progenitors (seen both at 10-12 days and at 17+ days but not at 5-7 days after a single TAM injection), along with an increase in the numbers of Paneth cells and goblet cells in proximal jejunal crypts

• 5 days after a single TAM injection, flow-sorted Lgr5+ ISC-derived tdTomato+ progeny show a modest increase in the fraction stem cells (35.34% vs 22.96% in controls), fewer transit-amplifying progenitors (18.40% vs 25.73% in controls) and a 5.8-fold increase in Paneth cells (7.88% vs 1.36% in controls), along with a weakened Lgr5+ stemness signature in ISCs but only minor effects on proliferation and apoptosis

• 12 days after a single TAM injection, crypt cells show induction of Atoh1 mRNA transcripts and reduction of Hes1 mRNA transcripts by ISH

• 17 days after a single TAM injection, no change in the proliferation or apoptosis of ISCs and progenitors is observed, and small intestine length, crypt depth, and numbers of chromogranin A+ enteroendocrine cells in jejunal crypts are normal

• TAM-treated mice show reduced numbers of H3K27ac-positive and Notch intracellular domain (NICD)-positive crypt cell nuclei, indicating increased class I histone deacetylase (HDAC) activity and less Notch signaling

• TAM treatment followed by administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of H3K27ac-positive and NICD-positive crypt cell nuclei to wild-type numbers

enhanced intestine regeneration ( J:280699 )

• when mice are fed a ketogenic diet (KTD) for 4 weeks, TAM-treated and then irradiated, the number of tdTomato+ crypts per mm jejunum is significantly higher than in chow-fed control mice, indicating enhanced regenerative output of tdTomato-labeled ISCs after injury

impaired intestine regeneration ( J:280699 )

• when mice are treated with TAM 1 day prior to radiation-induced intestinal epithelial injury, ISCs generate 5-fold less labeled tdTomato+ crypts with fewer Lgr5+ ISC-derived labeled progeny extending up crypt-villous units at 5 days post-radiation, and the overall number of surviving intact jejunal crypts is reduced by 2-fold

• oral administration of poly(lactic-co-glycolic acid) (PLGA) encapsulated beta-hydroxybutyrate (beta-OHB) nanoparticles or betaOHB oligomers partially rescues intestinal regeneration after radiation-induced damage

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) rescues the decline in ISC numbers and ISC function after radiation-induced injury

endocrine/exocrine glands

increased Paneth cell number ( J:280699 )

• 12 and >22 days after a single TAM injection, mice show a significant increase in the number of LYZ1+ Paneth cells in proximal jejunal crypts

• 5 days after a single TAM injection, flow-sorted Lgr5+ ISC-derived tdTomato+ progeny show a 5.8-fold increase in Paneth cells (7.88% vs 1.36% in controls)

• as early 24 h after TAM injection, ISCs generate significantly greater numbers of tdTomato+ Paneth cells in jejunal sections

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of LYZ+ Paneth cells in proximal jejunal crypts

abnormal jejunum crypts of Lieberkuhn morphology ( J:280699 )

• TAM-treated mice show a progressive loss of OLFM4+ intestinal stem cells (ISCs) and early progenitors (seen both at 10-12 days and at 17+ days but not at 5-7 days after a single TAM injection), along with an increase in the numbers of Paneth cells and goblet cells in proximal jejunal crypts

• 5 days after a single TAM injection, flow-sorted Lgr5+ ISC-derived tdTomato+ progeny show a modest increase in the fraction stem cells (35.34% vs 22.96% in controls), fewer transit-amplifying progenitors (18.40% vs 25.73% in controls) and a 5.8-fold increase in Paneth cells (7.88% vs 1.36% in controls), along with a weakened Lgr5+ stemness signature in ISCs but only minor effects on proliferation and apoptosis

• 12 days after a single TAM injection, crypt cells show induction of Atoh1 mRNA transcripts and reduction of Hes1 mRNA transcripts by ISH

• 17 days after a single TAM injection, no change in the proliferation or apoptosis of ISCs and progenitors is observed, and small intestine length, crypt depth, and numbers of chromogranin A+ enteroendocrine cells in jejunal crypts are normal

• TAM-treated mice show reduced numbers of H3K27ac-positive and Notch intracellular domain (NICD)-positive crypt cell nuclei, indicating increased class I histone deacetylase (HDAC) activity and less Notch signaling

• TAM treatment followed by administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of H3K27ac-positive and NICD-positive crypt cell nuclei to wild-type numbers

homeostasis/metabolism

abnormal response to radiation ( J:280699 )

• mice treated with TAM 1 day prior to radiation-induced intestinal epithelial injury show impaired Lgr5+ ISC-mediated repair in jejunal crypts relative to controls

• oral administration of nanoparticle PLGA-encapsulated beta-OHB or betaOHB oligomers partially rescues intestinal regeneration after radiation-induced damage

• when mice are fed a ketogenic diet (KTD) for 4 weeks, TAM-treated and then irradiated, the number of tdTomato+ crypts per mm jejunum is significantly higher than in chow-fed controls, indicating enhanced regenerative output of tdTomato-labeled ISCs after injury

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) rescues the decline in ISC numbers and ISC function after radiation-induced injury

cellular

abnormal jejunal goblet cell morphology ( J:280699 )

• 12 days after a single TAM injection, mice show a significant increase in the number of mucin+ goblet cells in proximal jejunal crypts

• TAM treatment followed administration of the HDAC inhibitor quisinostat (JNJ, 1 mg/kg, 5 i.p. injections) restores the number of AB/PAS+ goblet cells in proximal jejunal crypts

abnormal intestinal crypt stem cell physiology ( J:280699 )

• when mice are treated with TAM 24 h prior to crypt isolation, ISCs cultured in standard medium are 34.4% less capable of forming organoids, with resulting organoids showing a 40.5% increase in goblet cells and a 64.3% decrease in tdTomato+ cells per organoid relative to controls

• exogenous beta-hydroxybutyrate (beta-OHB), but not lactate (a Paneth niche-derived metabolite that sustains ISC function), restores the organoid-forming capacity and generation of tdTomato + clones and rescues the secretory lineage bias

Genotype
MGI:8159406

cn3

• Allelic Composition: Hmgcs2^tm1.1Yil/Hmgcs2^tm1.1Yil; Tg(Vil1-cre/ERT2)23Syr/0
• Genetic Background: involves: C3H * C57BL/6 * C57BL/6J * DBA/2

mortality/aging

decreased survivor rate ( J:280699 )

• only ~55% of mice survive 25-30 days after the first TAM injection is administered at P7

premature death ( J:280699 )

• mice exhibit increased mortality 15 days after the first tamoxifen (TAM) injection is administered at P7, reaching ~45% mortality by 25 days post-injection

growth/size/body

decreased body weight ( J:280699 )

• body weight is modestly decreased 15 days after the first TAM injection

digestive/alimentary system

abnormal jejunal goblet cell morphology ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold increase in the numbers of mucin+ (Alcian blue+) goblet cells in proximal jejunal crypts

decreased intestinal crypt stem cell number ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold reduction in the numbers of OLFM4+ cells, a marker co-expressed by Lgr5+ ISCs and early progenitors, in proximal jejunal crypts

increased Paneth cell number ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold increase in the numbers of lysozyme 1 (LYZ1)+ Paneth cells in proximal jejunal crypts

abnormal jejunum crypts of Lieberkuhn morphology ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold reduction in the numbers of olfactomedin 4-positive (OLFM4+) cells, a marker co-expressed by Lgr5+ intestinal stem cells (ISCs) and early progenitors, along with a >2-fold increase in the numbers of Paneth cells and goblet cells in proximal jejunal crypts, suggesting that differentiation of ISCs is skewed toward the secretory lineage

enhanced intestine regeneration ( J:280699 )

• when TAM-treated mice are fed a ketogenic diet (KTD) for 3 weeks and irradiated, the overall number of surviving intact jejunal crypts is significantly higher than that in chow-fed control mice

endocrine/exocrine glands

decreased intestinal crypt stem cell number ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold reduction in the numbers of OLFM4+ cells, a marker co-expressed by Lgr5+ ISCs and early progenitors, in proximal jejunal crypts

increased Paneth cell number ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold increase in the numbers of lysozyme 1 (LYZ1)+ Paneth cells in proximal jejunal crypts

abnormal jejunum crypts of Lieberkuhn morphology ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold reduction in the numbers of olfactomedin 4-positive (OLFM4+) cells, a marker co-expressed by Lgr5+ intestinal stem cells (ISCs) and early progenitors, along with a >2-fold increase in the numbers of Paneth cells and goblet cells in proximal jejunal crypts, suggesting that differentiation of ISCs is skewed toward the secretory lineage

homeostasis/metabolism

abnormal homeostasis ( J:280699 )

• intestinal crypts isolated from TAM-treated mice show progressively lower beta-hydroxybutyrate (beta-OHB) levels at 24 h, 7 days, and 12 days after the first TAM injection

• reduced crypt betaOHB levels correlate with a decline in mRNA expression of Hes1 (a Notch target gene) over time; however, TAM-treated mice show normal hepatic HMGCS2 protein expression and serum betaOHB levels, and no effect on intestinal CPT1A (carnitine palmitoyltransferase 1a, liver) protein levels or on fatty acid oxidation in crypt cells is observed

• when TAM-treated mice are fed a ketogenic diet (KTD) for 3 weeks and irradiated, crypt betaOHB levels are significantly lowered and still higher than those in chow-fed control mice

cellular

abnormal jejunal goblet cell morphology ( J:280699 )

• at 37 days of age, TAM-treated mice show a >2-fold increase in the numbers of mucin+ (Alcian blue+) goblet cells in proximal jejunal crypts