Search

With recent advances in technologies to profile multi‐omics data at the single‐cell level, integrative multi‐omics data analysis has been increasingly popular. It is increasingly common that information such as methylation changes, chromatin accessibility, and gene expression are jointly collected in a single‐cell experiment. In biomedical studies, it is often of interest to study the associations between various data types and to examine how these associations might change according to other factors such as cell types and gene regulatory components. However, since each data type usually has a distinct marginal distribution, joint analysis of these changes of associations using multi‐omics data is statistically challenging. In this paper, we propose a flexible copula‐based framework to model covariate‐dependent correlation structures independent of their marginals. In addition, the proposed approach could jointly combine a wide variety of univariate marginal distributions, either discrete or continuous, including the class of zero‐inflated distributions. The performance of the proposed framework is demonstrated through a series of simulation studies. Finally, it is applied to a set of experimental data to investigate the dynamic relationship between single‐cell RNA sequencing, chromatin accessibility, and DNA methylation at different germ layers during mouse gastrulation. [ABSTRACT FROM AUTHOR]

This article, titled "Editorial: New advances on hypothalamus-pituitary stem cell biology," discusses recent advancements in the understanding of stem cells in the pituitary and hypothalamus and their potential for regenerative medicine. The authors highlight the gaps in knowledge regarding the molecular mechanisms that regulate the differentiation of these stem cells into specific cell types. The article also explores the role of genetic variants in hypothalamic-pituitary diseases and the challenges in generating pituitary organoids for therapeutic purposes. Additionally, the authors discuss the activation of endogenous pituitary stem cells and the potential role of cytokines in this process. Overall, this research provides valuable insights into hypothalamic and pituitary stem cells and their potential for future stem cell therapies. [Extracted from the article]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.08.046 Byline: Michelle L. Brinkmeier, Mary Anne Potok, Shannon W. Davis, Sally A. Camper Keywords: Pituitary; Patterning; Wnt signaling; Organogenesis; TCF; BMP; FGF Abstract: The anterior and intermediate lobes of the pituitary gland are formed from Rathke's pouch. FGF, BMP and WNT signals emanating from the ventral diencephalon influence pouch growth and development. In order to examine the role of canonical WNT signaling during pituitary development we examined the pituitary expression of the TCF/LEF family of transcription factors, which mediate WNT signaling through the binding of [beta]-catenin. We report here the expression of several members of this family during pituitary development and the functional role of one member, TCF4 (TCF7L2), in the induction of the pituitary primordium. TCF4 is expressed in the ventral diencephalon early in pituitary development, rostral to a domain of BMP and FGF expression. Tcf4 deficient mice express Fgf10 and Bmp4; however, the Bmp and Fgf expression domains are expanded rostrally. As a result, additional pituitary progenitor cells are recruited into Rathke's pouch in Tcf4 mutants. Mutants also exhibit an expansion of the Six6 expression domain within Rathke's pouch, which may increase the number of proliferating pouch cells, resulting in a greatly enlarged anterior pituitary gland. This suggests that TCF4 negatively regulates pituitary growth through two mechanisms. The first mechanism is to restrict the domains of BMP and FGF signaling in the ventral diencephalon, and the second mechanism is the restriction of Six6 within Rathke's pouch. Thus, TCF4 is necessary both intrinsically and extrinsically to Rathke's pouch to ensure the proper growth of the pituitary gland. Author Affiliation: University of Michigan, Department of Human Genetics, 4909 Buhl Building, 1241 E. Catherine, Ann Arbor, MI 48109-0618, USA Article History: Received 5 October 2006; Revised 22 August 2007; Accepted 23 August 2007

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2007.02.001 Byline: Shannon W. Davis, Sally A. Camper Keywords: Ventral diencephalon; Rathke's pouch; Dorsal-ventral patterning; Ectopic pituitary gland Abstract: Bone morphogenetic protein (Bmp) signaling is critical for the development and patterning of the mouse pituitary from the initial induction of Rathke's pouch to cell specification in the anterior lobe. We examined the regulation of Bmp signaling during pituitary development by analyzing null embryos for noggin, a Bmp 2 and 4 antagonist. Noggin is expressed in the ventral diencephalon during Rathke's pouch induction, in the underlying cartilage plate during cell specification and in the adult anterior pituitary gland. Noggin null embryos have a variable pituitary phenotype, which ranges from a rostrally displaced Rathke's pouch to induction of secondary pituitary tissue. While cell specification in the anterior pituitary appears normal, patterning in the ventral diencephalon is disrupted; Bmp4 activity is expanded resulting in Fibroblast growth factor 10 repression and in a rostral shift in the boundary between the Bmp4 and Sonic hedgehog expression domains. The expanded domain of Bmp4 activity also results in additional invaginations of oral ectoderm and can shift the position of Rathke's pouch or create secondary pituitary tissue. This work demonstrates the importance of attenuating the activity of Bmp signaling during pituitary induction in order to maintain the proper balance of signaling factors necessary for pituitary organogenesis. Author Affiliation: Department of Human Genetics, University of Michigan Medical School, 4909 Buhl Building, 1241 E. Catherine St., Ann Arbor, MI 48109-0618, USA Article History: Received 3 March 2006; Revised 31 January 2007; Accepted 1 February 2007

RBX1 (RING box protein-i) or ROC1 (regulator of cullins-1) is the RING component of SCF (Skpl, Cullins,F-box proteins) E3 ubiquitin ligases, which regulate diverse cellular processes by targeting various substrates for degradation. However, the in vivo physiological function of RBX1 remains uncharacterized. Here, we show that a gene trap disruption of mouse Rbx1 causes embryonic lethality at embryonic day (E)7.5, mainly due to a failure in proliferation; p27, a cyclin dependent kinase inhibitor, normally undetectable in the early embryos, accumulates at high levels in the absence of Rbx1. Although mice heterozygous for the Rbxl gene trap appear viable and fertile without obvious abnormalities, the Rbx1[sup+/Gt] MEFs do show retarded growth with G1 arrest and p27 accumulation. Simultaneous loss of p27 extended the life span of Rbx1[supGt/Gt] embryos from E6.5 to E9.5, indicating that p27mediated cell cycle inhibition contributes to the early embryonic lethality in the Rbx1-deficient embryos. Our study demonstrates that the in vivo physiological function of RBX1 is to ensure cell proliferation by preventing p27 accumulation during the early stage of embryonic development. [ABSTRACT FROM AUTHOR]

RNA interference (RNAi) is a powerful strategy for studying the phenotypic consequences of reduced gene expression levels in model systems. To develop a method for the rapid characterization of the developmental consequences of gene dysregulation, we tested the use of RNAi for “transient transgenic” knockdown of mRNA in mouse embryos. These methods included lentiviral infection as well as transposition using the Sleeping Beauty (SB) and PiggyBac (PB) transposable element systems. This approach can be useful for phenotypic validation of putative mutant loci, as we demonstrate by confirming that knockdown of Prdm16 phenocopies the ENU-induced cleft palate (CP) mutant, csp1. This strategy is attractive as an alternative to gene targeting in embryonic stem cells, as it is simple and yields phenotypic information in a matter of weeks. Of the three methodologies tested, the PB transposon system produced high numbers of transgenic embryos with the expected phenotype, demonstrating its utility as a screening method.

Mutations in Prkra gene, which encodes PACT/RAX cause early onset primary dystonia DYT-PRKRA, a movement disorder that disrupts coordinated muscle movements. PACT/RAX activates protein kinase R (PKR, aka EIF2AK2) by a direct interaction in response to cellular stressors to mediate phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α). Mice homozygous for a naturally arisen, recessively inherited frameshift mutation, Prkra lear-5J exhibit progressive dystonia. In the present study, we investigate the biochemical and developmental consequences of the Prkra lear-5J mutation. Our results indicate that the truncated PACT/RAX protein retains its ability to interact with PKR, however, it inhibits PKR activation. Furthermore, mice homozygous for the mutation have abnormalities in the cerebellar development as well as a severe lack of dendritic arborization of Purkinje neurons. Additionally, reduced eIF2α phosphorylation is noted in the cerebellums and Purkinje neurons of the homozygous Prkra lear-5J mice. These results indicate that PACT/RAX mediated regulation of PKR activity and eIF2α phosphorylation plays a role in cerebellar development and contributes to the dystonia phenotype resulting from this mutation., Competing Interests: Financial Disclosure/Conflict of Interest: The authors declare no financial disclosures or conflicts of interest.

Many aspects of pituitary development have become better understood in the past two decades. The signaling pathways regulating pituitary growth and shape have emerged, and the balancing interactions between the pathways are now appreciated. Markers for multipotent progenitor cells are being identified, and signature transcription factors have been discovered for most hormone-producing cell types. We now realize that pulsatile hormone secretion involves a 3D integration of cellular networks. About a dozen genes are known to cause pituitary hypoplasia when mutated due to their essential roles in pituitary development. Similarly, a few genes are known that predispose to familial endocrine neoplasia, and several genes mutated in sporadic pituitary adenomas are documented. In the next decade, we anticipate gleaning a deeper appreciation of these processes at the molecular level, insight into the development of the hypophyseal portal blood system, and evolution of better therapeutics for congenital and acquired hormone deficiencies and for common craniopharyngiomas and pituitary adenomas., (© 2013 Elsevier Inc. All rights reserved.)