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Richard N Freiman

Publications and source records attributed to Richard N Freiman.

6 recordsLinked to original sources
PubMed2006

Ovarian granulosa cell survival and proliferation requires the gonad-selective TFIID subunit TAF4b.

Oocyte development in the mammalian ovary requires productive interactions with somatic granulosa cells of the ovarian follicle. Proliferating granulosa cells support the progression of follicular growth and maturation, multiplying dramatically as it unfolds. The cell cycle recruitment of granulosa cells is regulated at least in part by hormones such as follicle-stimulating hormone (FSH) and estrogen. Follicles recruited into the growth phase following formation of multiple layers of granulosa cells have two major fates: either to continue proliferation followed by differentiation, or to die by programmed cell death, or atresia. While many of the signaling pathways orchestrating ovarian follicle development are known, the downstream transcriptional regulators that integrate such signals in the mammalian ovary remain to be defined. Recent experiments in diverse organisms have revealed multiple instances of gonad-selective components of the basal transcriptional machinery. One such protein, TAF4b, is a gonadal-enriched coactivator subunit of the TFIID complex required for normal female fertility in the mouse. To determine the etiology of female infertility of the TAF4b-deficient mice, we have determined multiple functions of TAF4b during postnatal ovarian follicle development. Here we demonstrate that the TAF4b protein is expressed in the granulosa cell compartment of the mammalian ovarian follicle. Furthermore, TAF4b-deficient mouse ovaries contain reduced numbers of primordial as well as growing follicles and a concomitant increased proportion of apoptotic follicles in comparison to wild type counterparts. Importantly, TAF4b-null follicles are largely resistant to induction of proliferation in response to multiple hormonal stimuli including estrogen and FSH and demonstrate compromised granulosa cell survival. Together, these data suggest that TAF4b integrates a program of granulosa cell gene expression required for normal ovarian follicle survival and proliferation in response to diverse ovarian signaling events.

Animals↗
PubMed2006

Cell-type-selective induction of c-jun by TAF4b directs ovarian-specific transcription networks.

Cell-type-selective expression of the TFIID subunit TAF(II)105 (renamed TAF4b) in the ovary is essential for proper follicle development. Although a multitude of signaling pathways required for folliculogenesis have been identified, downstream transcriptional integrators of these signals remain largely unknown. Here, we show that TAF4b controls the granulosa-cell-specific expression of the proto-oncogene c-jun, and together they regulate transcription of ovary-selective promoters. Instead of using cell-type-specific activators, our findings suggest that the coactivator TAF4b regulates the expression of tissue-specific genes, at least in part, through the cell-type-specific induction of c-jun, a ubiquitous activator. Importantly, the loss of TAF4b in ovarian granulosa cells disrupts cellular morphologies and interactions during follicle growth that likely contribute to the infertility observed in TAF4b-null female mice. These data highlight a mechanism for potentiating tissue-selective functions of the basal transcription machinery and reveal intricate networks of gene expression that orchestrate ovarian-specific functions and cell morphology.

Animals↗
PubMed2005

Maintenance of spermatogenesis requires TAF4b, a gonad-specific subunit of TFIID.

The establishment and maintenance of spermatogenesis in mammals requires specialized networks of gene expression programs in the testis. The gonad-specific TAF4b component of TFIID (formerly TAF(II)105) is a transcriptional regulator enriched in the mouse testis. Herein we show that TAF4b is required for maintenance of spermatogenesis in the mouse. While young Taf4b-null males are initially fertile, Taf4b-null males become infertile by 3 mo of age and eventually exhibit seminiferous tubules devoid of germ cells. At birth, testes of Taf4b-null males appear histologically normal; however, at post-natal day 3 gonocyte proliferation is impaired and expression of spermatogonial stem cell markers c-Ret, Plzf, and Stra8 is reduced. Together, these data indicate that TAF4b is required for the precise expression of gene products essential for germ cell proliferation and suggest that TAF4b may be required for the regulation of spermatogonial stem cell specification and proliferation that is obligatory for normal spermatogenic maintenance in the adult.

Aging↗
PubMed2003

Regulating the regulators: lysine modifications make their mark.

Decades of research have uncovered much of the molecular machinery responsible for establishing and maintaining proper gene transcription patterns in eukaryotes. Although the composition of this machinery is largely known, mechanisms regulating its activity by covalent modification are just coming into focus. Here, we review several cases of ubiquitination, sumoylation, and acetylation that link specific covalent modification of the transcriptional apparatus to their regulatory function. We propose that potential cascades of modifications serve as molecular rheostats that fine-tune the control of transcription in diverse organisms.

Acetylation↗
PubMed2002

Redundant role of tissue-selective TAF(II)105 in B lymphocytes.

Regulated gene expression is a complex process achieved through the function of multiple protein factors acting in concert at a given promoter. The transcription factor TFIID is a central component of the machinery regulating mRNA synthesis by RNA polymerase II. This large multiprotein complex is composed of the TATA box binding protein (TBP) and several TBP-associated factors (TAF(II)s). The recent discovery of multiple TBP-related factors and tissue-specific TAF(II)s suggests the existence of specialized TFIID complexes that likely play a critical role in regulating transcription in a gene- and tissue-specific manner. The tissue-selective factor TAF(II)105 was originally identified as a component of TFIID derived from a human B-cell line. In this report we demonstrate the specific induction of TAF(II)105 in cultured B cells in response to bacterial lipopolysaccharide (LPS). To examine the in vivo role of TAF(II)105, we have generated TAF(II)105-null mice by homologous recombination. Here we show that B-lymphocyte development is largely unaffected by the absence of TAF(II)105. TAF(II)105-null B cells can proliferate in response to LPS, produce relatively normal levels of resting antibodies, and can mount an immune response by producing antigen-specific antibodies in response to immunization. Taken together, we conclude that the function of TAF(II)105 in B cells is likely redundant with the function of other TAF(II)105-related cellular proteins.

Animals↗