Gonadotropin-releasing hormone (GnRH) is the central regulator of the hypothalamic-pituitary-gonadal axis, controlling sexual maturation and fertility in diverse species from fish to humans. GnRH gene expression is limited to a discrete population of neurons that migrate through the nasal region into the hypothalamus during embryonic development. The GnRH regulatory region contains four conserved homeodomain binding sites (ATTA) that are essential for basal promoter activity and cell-specific expression of the GnRH gene. MSX and DLX are members of the Antennapedia class of non-Hox homeodomain transcription factors that regulate gene expression and influence development of the craniofacial structures and anterior forebrain. Here, we report that expression patterns of the Msx and Dlx families of homeodomain transcription factors largely coincide with the migratory route of GnRH neurons and co-express with GnRH in neurons during embryonic development. In addition, MSX and DLX family members bind directly to the ATTA consensus sequences and regulate transcriptional activity of the GnRH promoter. Finally, mice lacking MSX1 or DLX1 and 2 show altered numbers of GnRH-expressing cells in regions where these factors likely function. These findings strongly support a role for MSX and DLX in contributing to spatiotemporal regulation of GnRH transcription during development.Proper sexual maturation and fertility are dependent upon the correct function of the hypothalamic-pituitary-gonadal axis, initiated by a small, yet critical population of gonadotropin-releasing hormone (GnRH) 1 neurons. The GnRH gene is expressed in a complex spatiotemporal manner during embryonic development and into postnatal life with several populations of GnRH-expressing neurons originating at different developmental stages and locations. These populations include the classical, septohypothalamic neurons, as well as populations in the lateral septum, posterior bed nucleus stria terminalis (pBNST), and tectum (1, 2). Although the role of each of these populations of GnRH-producing neurons remains to be elucidated, the contribution of the septohypothalamic population is required for maturation of the hypothalamic-pituitarygonadal axis and fertility (3).The precursor cells of the septohypothalamic GnRH neurons have been reported to originate within the olfactory placode (4 -6) or the neural crest (7) and begin to express the GnRH transcript in a discrete population of cells located in close proximity to the olfactory placode of the embryonic mouse by 11.5-days postcoitum (11.5 dpc). By 12.5 dpc, the full complement of septohypothalamic GnRH neurons (ϳ800) in the adult population is established (6), and over the course of the next several days, these neurons migrate toward the CNS, closely associated with the established position of the peripherin-positive nerve bundle of the olfactory nerve (8, 9). By 16.5 dpc the majority of the septohypothalamic neurons have reached their destination, scattered throughout the preoptic area, the diagonal band of Broc...

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Equity is a core value of Health Impact Assessment (HIA). Many compelling moral, economic, and health arguments exist for prioritizing and incorporating equity considerations in HIA practice. Decision-makers, stakeholders, and HIA practitioners see the value of HIAs in uncovering the impacts of policy and planning decisions on various population subgroups, developing and prioritizing specific actions that promote or protect health equity, and using the process to empower marginalized communities. There have been several HIA frameworks developed to guide the inclusion of equity considerations. However, the field lacks clear indicators for measuring whether an HIA advanced equity. This article describes the development of a set of equity metrics that aim to guide and evaluate progress toward equity in HIA practice. These metrics also intend to further push the field to deepen its practice and commitment to equity in each phase of an HIA. Over the course of a year, the Society of Practitioners of Health Impact Assessment (SOPHIA) Equity Working Group took part in a consensus process to develop these process and outcome metrics. The metrics were piloted, reviewed, and refined based on feedback from reviewers. The Equity Metrics are comprised of 23 measures of equity organized into four outcomes: (1) the HIA process and products focused on equity; (2) the HIA process built the capacity and ability of communities facing health inequities to engage in future HIAs and in decision-making more generally; (3) the HIA resulted in a shift in power benefiting communities facing inequities; and (4) the HIA contributed to changes that reduced health inequities and inequities in the social and environmental determinants of health. The metrics are comprised of a measurement scale, examples of high scoring activities, potential data sources, and example interview questions to gather data and guide evaluators on scoring each metric.

Gonadotropin-releasing hormone (GnRH) is exclusively expressed in a unique population of hypothalamic neurons that controls reproductive function. GnRH gene expression is highly dynamic. Its transcriptional activity is regulated in a complex spatiotemporal manner during embryonic development and postnatal life. Although a variety of transcription factors have been identified as regulators of GnRH transcription, most are promiscuous in their DNA-binding requirements, and none are solely expressed in GnRH neurons. Their specific activity is probably determined by interactions with distinct cofactors. Here we find that the Grouchorelated gene (GRG) family of co-repressors is expressed in a model cell line for the GnRH neuron and co-expresses with GnRH during prenatal development. GRG proteins associate in vivo with the GnRH promoter. Furthermore, GRG proteins interact with two regulators of GnRH transcription, the homeodomain proteins MSX1 and OCT1. Co-transfection experiments indicate that GRG proteins regulate GnRH promoter activity. The long GRG forms enhance MSX1 repression and counteract OCT1 activation of the GnRH gene. In contrast, the short form, GRG5, has a dominant-negative effect on MSX1-dependent repression. Taken together, these data suggest that the dynamic switch between activation and repression of GnRH transcription is mediated by recruitment of the GRG co-regulators.The formation of unique transcription factor complexes determines the intricate spatial and temporal expression of genes during development as well as in terminal differentiation (1). An example of combinatorial regulation by multiple factors can be seen in cell-specific transcription of the gonadotropin-releasing hormone (GnRH) 1 gene. GnRH, a central regulator of the hypothalamic-pituitary-gonadal axis of the reproductive system, is expressed in a discrete population of neuronal cells (2). These neurons, scattered throughout the basal hypothalamus in the adult (3), release GnRH in a pulsatile manner. Due to the difficulties in studying the small and dispersed population of GnRH neurons, cultured cell models for GnRH neurons, the GT1-7 and NLT/Gn11 cell lines, were developed by targeted oncogenesis (4, 5). These model cell lines provided the first insight into the transcriptional regulation of GnRH expression. Using these models, evolutionarily conserved enhancer and promoter elements conferring neuron-specific activation in culture were identified (Ϫ1863 to Ϫ1571 and Ϫ173 to ϩ1, respectively, in the rat sequence) (6 -9). Furthermore, these regulatory sequences were sufficient for targeting a substantial population of GnRH neurons in transgenic mice (10 -14).

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproductive function. Expression of the GnRH gene is confined to a rare population of neurons scattered throughout the hypothalamus. Restricted expression of the rat GnRH gene is driven by a multicomponent enhancer and an evolutionarily conserved promoter. Oct-1, a ubiquitous POU homeodomain transcription factor, was identified as an essential factor regulating GnRH transcription in the GT1-7 hypothalamic neuronal cell line. In this study, we conducted a two-hybrid interaction screen in yeast using a GT1-7 cDNA library to search for specific Oct-1 cofactors. Using this approach, we isolated Pbx1b, a TALE homeodomain transcription factor that specifically associates with Oct-1. We show that heterodimers containing Pbx/ Prep1 or Pbx/Meis1 TALE homeodomain proteins bind to four functional elements within the GnRH regulatory region, each in close proximity to an Oct-1-binding site. Cotransfection experiments indicate that TALE proteins are essential for GnRH promoter activity in the GT1-7 cells. Moreover, Pbx1 and Oct-1, as well as Prep1 and Oct-1, form functional complexes that enhance GnRH gene expression. Finally, Pbx1 is expressed in GnRH neurons in embryonic as well as mature mice, suggesting that the associations between TALE homeodomain proteins and Oct-1 regulate neuron-specific expression of the GnRH gene in vivo.