Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors.
The Insm1 gene encodes a zinc finger factor expressed in many endocrine organs. We show here that Insm1 is required for differentiation of all endocrine cells in the pituitary. Thus, in Insm1 mutant mice, hormones characteristic of the different pituitary cell types (thyroid-stimulating hormone, follicle-stimulating hormone, melanocyte-stimulating hormone, adrenocorticotrope hormone, growth hormone and prolactin) are absent or produced at markedly reduced levels. This differentiation deficit is accompanied by upregulated expression of components of the Notch signaling pathway, and by prolonged expression of progenitor markers, such as Sox2. Furthermore, skeletal muscle-specific genes are ectopically expressed in endocrine cells, indicating that Insm1 participates in the repression of an inappropriate gene expression program. Because Insm1 is also essential for differentiation of endocrine cells in the pancreas, intestine and adrenal gland, it is emerging as a transcription factor that acts in a pan-endocrine manner. The Insm1 factor contains a SNAG domain at its N-terminus, and we show here that the SNAG domain recruits histone-modifying factors (Kdm1a, Hdac1/2 and Rcor1-3) and other proteins implicated in transcriptional regulation (Hmg20a/b and Gse1). Deletion of sequences encoding the SNAG domain in mice disrupted differentiation of pituitary endocrine cells, and resulted in an upregulated expression of components of the Notch signaling pathway and ectopic expression of skeletal muscle-specific genes. Our work demonstrates that Insm1 acts in the epigenetic and transcriptional network that controls differentiation of endocrine cells in the anterior pituitary gland, and that it requires the SNAG domain to exert this function in vivo.
Developmental Biology/Signal Transduction Group, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Jochen E
JE
Welcker
Luis R
LR
Hernandez-Miranda
Florian E
FE
Paul
Shiqi
S
Jia
Andranik
A
Ivanov
Matthias
M
Selbach
Carmen
C
Birchmeier
D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055098:Endocrine Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006609:High Mobility Group Proteins / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D006657:Histones; C507322:Hmg20a protein, mouse; C400291:Hmg20b protein, mouse; C477059:Insm1 protein, mouse; D009419:Nerve Tissue Proteins; C000589468:Rcor1 protein, mouse; C485650:Rcor2 protein, mouse; D051880:Receptors, Notch; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
Differentiation; Hormone; Kdm1a; Mouse