Mammalian Heat Shock Factor 1 Is Essential for Oocyte Meiosis and Directly Regulates Hsp90α Expression

Abstract

Heat shock transcription factor 1 (HSF1) is the main regulator of the stress response that triggers the transcription of several genes encoding heat shock proteins (Hsps). Hsps act as molecular chaperones involved in protein folding, stability, and trafficking. HSF1 is highly expressed in oocytes and Hsf1 knock-out in mice revealed that in the absence of stress this factor plays an important role in female reproduction. We previously reported that Hsf1؊/؊ females produce oocytes but no viable embryos. Consequently, we asked whether oocytes require HSF1 to regulate a particular set of Hsps necessary for them to develop. We find that Hsp90␣ (Hspaa1) is the major HSF1-dependent chaperone inasmuch as Hsf1 knock-out resulted in Hsp90-depleted oocytes. These oocytes exhibited delayed germinal vesicle breakdown (or G 2 /M transition), partial meiosis I block, and defective asymmetrical division. To probe the role of Hsp90␣ in this meiotic syndrome, we analyzed meiotic maturation in wildtype oocytes treated with a specific inhibitor of Hsp90, 17-allylamino-17-demethoxy-geldanamycin, and observed similar defects. At the molecular level we showed that, together with these developmental anomalies, CDK1 and MAPK, key meiotic kinases, were significantly disturbed. Thus, our data demonstrate that HSF1 is a maternal transcription factor essential for normal progression of meiosis.In mammals there are several heat shock factors (HSF1, -2, and -4) 3 that share a similar DNA binding domain, but HSF1 appears to be the major transcriptional regulator responsible for the stress-inducible expression of heat shock proteins (Hsps) (1, 2). The Hsf1 gene was targeted by homologous recombination in murine ES cells, and Hsf1 knock-out mice were produced by three different laboratories (3-5). Gene expression analyses in various cell types, and organs derived from these Hsf1 Ϫ/Ϫ mice revealed that HSF1 also regulates Hsp in physiological conditions (6 -8), providing accumulating evidence for the important function of HSF1 in maintaining cell homeostasis. Furthermore, those analyses and genome-wide screen demonstrated that numerous genes that were not classified as Hsps appeared to be HSF1-dependent (8, 9). Thus, HSF1 is clearly not restricted to the control of Hsp expression or the heat shock response. As shown by the complex phenotype of Hsf1 knock-out mice, HSF1 is involved in several specialized cell functions (e.g. placenta formation, immunity, placode development, cancer cell viability) (3, 5, 10, 11) and is essential for female reproduction (3). We showed previously that Hsf1 Ϫ/Ϫ female infertility is linked to the inability of Hsf1 Ϫ/Ϫ oocytes to produce viable embryos after natural mating (12). Nevertheless, the molecular and cellular mechanisms affected by the loss of HSF1 function in oocytes required further investigation to be better understood.Because HSF1 is highly expressed in oocytes, we hypothesized that it could regulate critical Hsps for the final development of oocytes into embryos. Although a series of studies separately ...

Portrait of an oocyte: our obscure origin

“…Mutations of maternal effect genes block mouse oocyte/embryo development between late oogenesis and the blastocyst stage (Table 1; refs. 41,[84][85][86][87][88][89][90][91][92][93], as does mutation of some genes expressed more widely, but only the former have effects specific to fertility. As examples of other oocyte-expressed genes, CCCTCbinding factor and postmeiotic segregation increased 2 (Pms2) are translated from mouse oocyte mRNAs needed for cleavage, but they are not considered products of maternal effect genes because they also have somatic functions including epigenome regulation (94) and DNA mismatch repair (95), respectively.…”

Maternal control of early mouse development

“…Heat shock factor 1 (HSF1), a master regulator of stress-inducible genes, is highly expressed in mouse oocytes. Although its expression is not limited to oocytes, Hsf1-null females have defects in meiosis (Metchat et al, 2009), and embryos derived from their ovulated eggs arrest, primarily at the 1-cell stage (Table 1) (Christians et al, 2000). Two zinc-finger transcription factors are also required for early embryogenesis.…”

Efectos de los RNAm maternos sobre la maduración del ovocito y el desarrollo embrionario temprano en mamíferos

“…HSF1, es un factor de transcripción que actúa como un gen maestro regulando la expresión de genes inducibles al estrés, y es altamente expresado en ovocitos de ratón. Aunque su expresión no está limitada a los ovocitos, hembras deficientes de este gen tienen defectos a nivel de la meiosis (109) y los embriones derivados de los ovocitos de estas hembras son arrestados en cigotos (110) . Basonuclina1, codificada por el RNAm materno bnc1, es un factor de transcripción con dominios de dedos de zinc, abundante en células germinales; actúa sobre la transcripción mediada por las enzimas RNA polimerasas I y II.…”

“…HSF1, is a transcription factor that acts as a master gene, regulating the expression of stress-inducible genes, and is highly expressed in mouse oocytes. Although its expression is not restricted to oocytes, deficient females of this gene have defects at the level of the meiosis (109) and embryos derived from oocytes of these females are arrested in zygotes (110) . Basonuclina1, encoded by the mRNA maternal bnc1, is a transcription factor with domains of zinc fingers, abundant in germinal cells; acts on transcription mediated by RNA polymerases enzymes I and II.…”