The zinc finger transcription factorGfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival

Abstract

Gfi1 was first identified as causing interleukin 2-independent growth in T cells and lymphomagenesis in mice. Much work has shown thatGfi1 and Gfi1b, a second mouse homolog, play pivotal roles in blood cell lineage differentiation. However, neither Gfi1 norGfi1b has been implicated in nervous system development, even though their invertebrate homologues, senseless in Drosophila andpag-3 in C. elegans are expressed and required in the nervous system. We show that Gfi1 mRNA is expressed in many areas that give rise to neuronal cells during embryonic development in mouse, and that Gfi1 protein has a more restricted expression pattern. By E12.5Gfi1 mRNA is expressed in both the CNS and PNS as well as in many sensory epithelia including the developing inner ear epithelia. At later developmental stages, Gfi1 expression in the ear is refined to the hair cells and neurons throughout the inner ear. Gfi1 protein is expressed in a more restricted pattern in specialized sensory cells of the PNS, including the eye, presumptive Merkel cells, the lung and hair cells of the inner ear.Gfi1 mutant mice display behavioral defects that are consistent with inner ear anomalies, as they are ataxic, circle, display head tilting behavior and do not respond to noise. They have a unique inner ear phenotype in that the vestibular and ccchlear hair cells are differentially affected. AlthoughGfi1-deficient mice initially specify inner ear hair cells, these hair cells are disorganized in both the vestibule and cochlea. The outer hair cells of the cochlea are improperly innervated and express neuronal markers that are not normally expressed in these cells. Furthermore, Gfi1mutant mice lose all cochlear hair cells just prior to and soon after birth through apoptosis. Finally, by five months of age there is also a dramatic reduction in the number of cochlear neurons. Hence, Gfi1 is expressed in the developing nervous system, is required for inner ear hair cell differentiation, and its loss causes programmed cell death.

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

“…28,31 In contrast, the number of Ash1 expressing cells in Gfi1 À/À mice remained the same. 28,31 As Ash1 is critically required for PNEC development, 34 Gfi1 might be required for maturation of presumptive PNEC.…”

“…27 Similar interactions between Gfi1 and proneural bHLH exist in the mammalian sensory organs such as the ear and the retina. [27][28][29][30] We recently reported the expression of Gfi1 and the proneural bHLH factor Achaete scute homolog-1 (mASH1) in both embryonic and adult mouse PNEC, and NE tumor cell lines. 28,31 Indeed, although Gfi1 deletion in mouse PNEC did not affect mASH1 expression, lack of Gfi1 resulted in dramatically reduced expression of NE markers such as calcitonin gene-related peptide (CGRP) and synaptophysin (SYN).…”

Hair Cell Generation by Notch Inhibition in the Adult Mammalian Cristae

“…To facilitate accurate hair cell counts, we used the nuclear hair cell marker Gfi1. Gfi1 is expressed in both the developing (Wallis et al 2003;Hertzano et al 2004;Yang et al 2010) and mature ( Fig. 1(B,C)) vestibular system.…”

Switch of rhodopsin expression in terminally differentiated Drosophila sensory neurons

“…The role of Sens in inhibiting apoptosis is not unique to this situation: Sens is essential to promote survival of salivary-gland precursors during embryogenesis 23 . The vertebrate homologue of sens, Gfi-1, acts to inhibit apoptosis of T-cell precursors in haematopoiesis and cochlear hair cells of the inner ear 24,25 . Thus the antiapoptotic function of Sens/Gfi-1 may be a general property of this molecule.…”