Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(alpha) orphan receptor.
The rev-erbA(alpha) gene, belonging to the steroid receptor superfamily of transcription factors, is highly conserved during evolution but little is known so far about its functions in development or in adult physiology. Here, we describe genetically altered mice lacking the rev-erbA(alpha) gene. These animals do not show any obvious phenotype in either fat tissue or skeletal muscle, despite the known regulation of rev-erbA(alpha) expression during adipocyte and myotube differentiation in vitro. However, during the second week of life, the cerebellum of rev-erbA(alpha) mutants presents several unexpected abnormalities, such as alterations in the development of Purkinje cells, delay in the proliferation and migration of granule cells from the external granule cell layer and increased apoptosis of neurons in the internal granule cell layer. Interestingly, the expression pattern of rev-erbA(alpha) suggests that the abnormalities observed in the external granule cell layer could be secondary to Purkinje cell alterations. Taken together, our data underline the importance of rev-erbA(alpha)expression for the appropriate balance of transcriptional activators and repressors during postnatal cerebellar development.
Chomez
P
P
Department of Cell and Molecular Biology and Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 77 Stockholm, Sweden.
Neveu
I
I
Mansén
A
A
Kiesler
E
E
Larsson
L
L
Vennström
B
B
Arenas
E
E
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002531:Cerebellum / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D018095:Germ-Line Mutation; D051379:Mice; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000166:cytology; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics
D004268:DNA-Binding Proteins; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone