Gfi1 and Gfi1b act equivalently in haematopoiesis, but have distinct, non‐overlapping functions in inner ear development

Abstract

Gfi1 is a transcriptional repressor essential for haematopoiesis and inner ear development. It shares with its paralogue Gfi1b an amino-terminal SNAG repressor domain and six carboxy-terminal zinc-finger motifs, but differs from Gfi1b in sequences separating these domains. Here, we describe two knock-in mouse models, in which the N-terminal SNAG repressor domain was mutated or in which the Gfi1 coding region was replaced by Gfi1b. Mouse mutants without an intact SNAG domain show the full phenotype of Gfi1 null mice. However, Gfi1:Gfi1b knock-in mice show almost normal pre-T-cell and neutrophil development, but lack properly formed inner ear hair cells. Hence, our findings show that an intact SNAG domain is essential for all functions of Gfi1 and that Gfi1b can replace Gfi1 functionally in haematopoiesis but, surprisingly, not in inner ear hair cell development, demonstrating that Gfi1 and Gfi1b have equivalent and domain-dependent, cell type-specific functions.

Ajuba Functions as a Histone Deacetylase-dependent Co-repressor for Autoregulation of the Growth Factor-independent-1 Transcription Factor

“…Thus, we hypothesized that Gfi1N382S sequesters limiting SNAG domain-associated factors. The requirement for SNAG-associated function in granulopoiesis is underscored by the Gfi1 Ϫ/Ϫ phenotype of mice with homozygous targeted knock in of a Gfi1P2A mutation (42). The current study shows that Ajuba acts as a co-repressor for the cognate DNA-bound Gfi1 protein, but that this interaction is not dependent upon the SNAG domain.…”

Gfi1 and Gfi1b: key regulators of hematopoiesis

“…Despite these differences, the insertion of Gfi1b coding sequences in the Gfi1 gene locus almost completely rescued the hematopoietic phenotypes observed in Gfi1-null mice. 8 This strongly suggests that the proteins exert similar molecular effects. However, a nonhematopoietic phenotype, loss of hearing, caused by a Gfi1 deficiency was not rescued by inserting Gfi1b in the Gfi1 gene locus, indicating that in certain other tissues these proteins function in a different way.…”

“…However, a nonhematopoietic phenotype, loss of hearing, caused by a Gfi1 deficiency was not rescued by inserting Gfi1b in the Gfi1 gene locus, indicating that in certain other tissues these proteins function in a different way. 8 Besides in inner ear development, Gfi1 also has a role in gut 9 and lung [10][11][12] development. Currently, it is unknown whether Gfi1b also has a role in the development of nonhematopoietic tissues.…”

Atoh1 in sensory hair cell development: constraints and cofactors

“…The SNAG domain is necessary for the recruitment of the LSD1/CoRest complex whilst interactions with other histonemodifying enzymes (HDACs and G9a) are mediated via the intermediary and zinc-finger regions of the Gfi1 protein (56,57). Despite these varied interactions, a single mutation in the SNAG domain, which disrupts the interactions with the LSD1/CoRest complex, leads to a phenotype apparently identical to that observed in Gfi1 null mice in both hematopoietic and non-hematopoietic systems (57,58). Further support for this mode of Gfi1 function comes from a recent study showing that LSD1 deficiency phenocopies the developmental arrest of the haematopoietic stem cells observed in Gfi1 null mice (59).…”

“…Gfi1b is important in hematopoiesis but is not required in hair cell development. Interestingly, when the Gfi1b coding region is knocked-in to the mutated Gfi1 locus, it can completely restore the defects in hematopoiesis, but not the defects in hair cell differentiation (58). Gfi1b shares high identity with Gfi1 in its SNAG and zinc finger domains and they are able to recognize the same DNA motif (62).…”