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BP1 is a negative modulator of definitive erythropoiesis.

Mpollo MS, Beaudoin M, Berg PE, Beauchemin H, D'Agati V, Trudel M - Nucleic Acids Res. (2006)

Bottom Line: Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality.In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation.These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Faculte de Medecine de l'Universite de Montreal, 110 ouest avenue des Pins, Montreal, Quebec, Canada H2W 1R7.

ABSTRACT
Beta protein 1 (BP1), a human homeotic transcription factor, is expressed during hematopoeisis in the erythroid lineage. To determine the in vivo role of BP1 in erythropoiesis, we have undertaken two complementary approaches using enforced BP1 expression in both transgenic mice and embryonic stem (ES) cells. Despite repeated attempts, only one adult transgenic BP1 founder mouse among 121 mice was obtained. This mouse presumably survived due to transgene mosaicism because the transgene could not be transmitted. This mouse expressed BP1 and displayed splenomegaly, extramedullary erythropoiesis and severe amyloidosis A in the kidney, a phenotype compatible with thalassemia. Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality. In ES cells, BP1 expression in primary differentiation appeared to antagonize adult beta-globin expression. In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation. These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

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Histopathological analysis of the LCRBP1 transgenic founder mouse. (a) Normal histology of the kidney displaying small regular glomeruli and surrounding tubulo-interstitial compartment (H&E, ×100). Inset shows glomerulus of normal size and cellularity with patent capillaries and basement membranes of normal thickness (H&E, ×400). (b) Renal histology of the transgenic LCRBP1 mouse showed diffuse and uniform enlargement of the glomeruli due to expansion of the glomerular tuft by amorphous pale eosinophilic material. The outlying tubules, interstitium and blood vessels are uninvolved (H&E, ×100). Inset shows a representative glomerulus of the transgenic LCRBP1 mouse with expansion of the mesangium and narrowing of the glomerular capillary lumina by voluminous deposits of amorphous material typical of amyloid. The glomerular cellularity appeared reduced (H&E, ×400). (c) Kidney of the transgenic LCRBP1 mouse viewed under polarized light displayed apple green birefringence diagnostic of amyloid deposits in a diffuse and global glomerular distribution (Congo red, polarized light, ×100). (d) Kidney of the transgenic LCRBP1 mouse showed strong diffuse and global glomerular positivity for serum amyloid A protein (SAA immunostain, ×250). (e) Ultrastructural analysis of a normal renal glomerular capillary showed the normal glomerular architecture, without fibrillar deposits (EM, ×6000). (f) Ultrastructure of a renal glomerulus from the transgenic LCRBP1 mouse showed abundant randomly oriented 8–10 nm fibrils expanding the mesangial regions and narrowing the adjacent glomerular capillary lumen (EM, ×6000). Inset shows fibrils at higher magnitude (EM, ×20 000).
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fig2: Histopathological analysis of the LCRBP1 transgenic founder mouse. (a) Normal histology of the kidney displaying small regular glomeruli and surrounding tubulo-interstitial compartment (H&E, ×100). Inset shows glomerulus of normal size and cellularity with patent capillaries and basement membranes of normal thickness (H&E, ×400). (b) Renal histology of the transgenic LCRBP1 mouse showed diffuse and uniform enlargement of the glomeruli due to expansion of the glomerular tuft by amorphous pale eosinophilic material. The outlying tubules, interstitium and blood vessels are uninvolved (H&E, ×100). Inset shows a representative glomerulus of the transgenic LCRBP1 mouse with expansion of the mesangium and narrowing of the glomerular capillary lumina by voluminous deposits of amorphous material typical of amyloid. The glomerular cellularity appeared reduced (H&E, ×400). (c) Kidney of the transgenic LCRBP1 mouse viewed under polarized light displayed apple green birefringence diagnostic of amyloid deposits in a diffuse and global glomerular distribution (Congo red, polarized light, ×100). (d) Kidney of the transgenic LCRBP1 mouse showed strong diffuse and global glomerular positivity for serum amyloid A protein (SAA immunostain, ×250). (e) Ultrastructural analysis of a normal renal glomerular capillary showed the normal glomerular architecture, without fibrillar deposits (EM, ×6000). (f) Ultrastructure of a renal glomerulus from the transgenic LCRBP1 mouse showed abundant randomly oriented 8–10 nm fibrils expanding the mesangial regions and narrowing the adjacent glomerular capillary lumen (EM, ×6000). Inset shows fibrils at higher magnitude (EM, ×20 000).

Mentions: The only adult female transgenic founder expressed BP1 in peripheral blood, shown by RT–PCR and Rnase protection (Figure 1b and data not shown). Pathological analysis upon the unexpected death of this transgenic founder mouse showed splenic enlargement by ∼2-fold compared to the age-matched control mouse strain. The bone marrow cellularity was increased by 1.8-fold in the femur of the founder mouse (8.4 × 107cells) relative to controls (4.6 × 107 ± 0.9 cells; n = 4) which is consistent with the ∼1.4-fold increase in cellularity observed in hemizygous β-globin knock-out mice, a model of β-thalassemia (15). Both these features are indicative of stimulated hematopoiesis and consistent with the observation of numerous foci of extramedullary hematopoiesis in organs such as spleen and kidney. While renal tissues had normal tubules, interstitium and blood vessels, the glomeruli showed expansion of the mesangium compared to controls (Figure 2a and b), with narrowing of the capillaries due to large Congo red positive amyloid deposits (Figure 2c and d). By specific staining for identification of amyloid precursor proteins, these amyloid deposits were negative for immunoglobulins, kappa and lambda light chains but positive for SAA (Figure 2c and d). Electron microscopy revealed glomerular deposits of randomly oriented 8–10 nm fibrils typical of amyloid (Figure 2e and f). Presence of increased SAA is observed in conditions of chronic inflammation as in thalassemia (16). The composite of these pathologic findings, increase in erythropoiesis/hematopoiesis and amyloid deposits, are consistent with a thalassemic condition in the BP1 transgenic mouse.


BP1 is a negative modulator of definitive erythropoiesis.

Mpollo MS, Beaudoin M, Berg PE, Beauchemin H, D'Agati V, Trudel M - Nucleic Acids Res. (2006)

Histopathological analysis of the LCRBP1 transgenic founder mouse. (a) Normal histology of the kidney displaying small regular glomeruli and surrounding tubulo-interstitial compartment (H&E, ×100). Inset shows glomerulus of normal size and cellularity with patent capillaries and basement membranes of normal thickness (H&E, ×400). (b) Renal histology of the transgenic LCRBP1 mouse showed diffuse and uniform enlargement of the glomeruli due to expansion of the glomerular tuft by amorphous pale eosinophilic material. The outlying tubules, interstitium and blood vessels are uninvolved (H&E, ×100). Inset shows a representative glomerulus of the transgenic LCRBP1 mouse with expansion of the mesangium and narrowing of the glomerular capillary lumina by voluminous deposits of amorphous material typical of amyloid. The glomerular cellularity appeared reduced (H&E, ×400). (c) Kidney of the transgenic LCRBP1 mouse viewed under polarized light displayed apple green birefringence diagnostic of amyloid deposits in a diffuse and global glomerular distribution (Congo red, polarized light, ×100). (d) Kidney of the transgenic LCRBP1 mouse showed strong diffuse and global glomerular positivity for serum amyloid A protein (SAA immunostain, ×250). (e) Ultrastructural analysis of a normal renal glomerular capillary showed the normal glomerular architecture, without fibrillar deposits (EM, ×6000). (f) Ultrastructure of a renal glomerulus from the transgenic LCRBP1 mouse showed abundant randomly oriented 8–10 nm fibrils expanding the mesangial regions and narrowing the adjacent glomerular capillary lumen (EM, ×6000). Inset shows fibrils at higher magnitude (EM, ×20 000).
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Related In: Results  -  Collection

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fig2: Histopathological analysis of the LCRBP1 transgenic founder mouse. (a) Normal histology of the kidney displaying small regular glomeruli and surrounding tubulo-interstitial compartment (H&E, ×100). Inset shows glomerulus of normal size and cellularity with patent capillaries and basement membranes of normal thickness (H&E, ×400). (b) Renal histology of the transgenic LCRBP1 mouse showed diffuse and uniform enlargement of the glomeruli due to expansion of the glomerular tuft by amorphous pale eosinophilic material. The outlying tubules, interstitium and blood vessels are uninvolved (H&E, ×100). Inset shows a representative glomerulus of the transgenic LCRBP1 mouse with expansion of the mesangium and narrowing of the glomerular capillary lumina by voluminous deposits of amorphous material typical of amyloid. The glomerular cellularity appeared reduced (H&E, ×400). (c) Kidney of the transgenic LCRBP1 mouse viewed under polarized light displayed apple green birefringence diagnostic of amyloid deposits in a diffuse and global glomerular distribution (Congo red, polarized light, ×100). (d) Kidney of the transgenic LCRBP1 mouse showed strong diffuse and global glomerular positivity for serum amyloid A protein (SAA immunostain, ×250). (e) Ultrastructural analysis of a normal renal glomerular capillary showed the normal glomerular architecture, without fibrillar deposits (EM, ×6000). (f) Ultrastructure of a renal glomerulus from the transgenic LCRBP1 mouse showed abundant randomly oriented 8–10 nm fibrils expanding the mesangial regions and narrowing the adjacent glomerular capillary lumen (EM, ×6000). Inset shows fibrils at higher magnitude (EM, ×20 000).
Mentions: The only adult female transgenic founder expressed BP1 in peripheral blood, shown by RT–PCR and Rnase protection (Figure 1b and data not shown). Pathological analysis upon the unexpected death of this transgenic founder mouse showed splenic enlargement by ∼2-fold compared to the age-matched control mouse strain. The bone marrow cellularity was increased by 1.8-fold in the femur of the founder mouse (8.4 × 107cells) relative to controls (4.6 × 107 ± 0.9 cells; n = 4) which is consistent with the ∼1.4-fold increase in cellularity observed in hemizygous β-globin knock-out mice, a model of β-thalassemia (15). Both these features are indicative of stimulated hematopoiesis and consistent with the observation of numerous foci of extramedullary hematopoiesis in organs such as spleen and kidney. While renal tissues had normal tubules, interstitium and blood vessels, the glomeruli showed expansion of the mesangium compared to controls (Figure 2a and b), with narrowing of the capillaries due to large Congo red positive amyloid deposits (Figure 2c and d). By specific staining for identification of amyloid precursor proteins, these amyloid deposits were negative for immunoglobulins, kappa and lambda light chains but positive for SAA (Figure 2c and d). Electron microscopy revealed glomerular deposits of randomly oriented 8–10 nm fibrils typical of amyloid (Figure 2e and f). Presence of increased SAA is observed in conditions of chronic inflammation as in thalassemia (16). The composite of these pathologic findings, increase in erythropoiesis/hematopoiesis and amyloid deposits, are consistent with a thalassemic condition in the BP1 transgenic mouse.

Bottom Line: Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality.In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation.These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Faculte de Medecine de l'Universite de Montreal, 110 ouest avenue des Pins, Montreal, Quebec, Canada H2W 1R7.

ABSTRACT
Beta protein 1 (BP1), a human homeotic transcription factor, is expressed during hematopoeisis in the erythroid lineage. To determine the in vivo role of BP1 in erythropoiesis, we have undertaken two complementary approaches using enforced BP1 expression in both transgenic mice and embryonic stem (ES) cells. Despite repeated attempts, only one adult transgenic BP1 founder mouse among 121 mice was obtained. This mouse presumably survived due to transgene mosaicism because the transgene could not be transmitted. This mouse expressed BP1 and displayed splenomegaly, extramedullary erythropoiesis and severe amyloidosis A in the kidney, a phenotype compatible with thalassemia. Consistently, the presence of BP1 transgene in fetuses was associated with paleness and lethality. In ES cells, BP1 expression in primary differentiation appeared to antagonize adult beta-globin expression. In secondary differentiation, BP1 expression reduced significantly beta-globin gene expression in both primitive and definitive erythroid cells, whereas it impaired only the definitive erythroid cell differentiation. These studies showed that BP1 can negatively modulate adult beta-globin gene expression and definitive erythroid cell differentiation, and suggest that BP1 could play a role in thalassemia.

Show MeSH
Related in: MedlinePlus