Tbx5 overexpression in embryoid bodies increases TAK1 expression but does not enhance the differentiation of sinoatrial node cardiomyocytes.

Genetic studies place Tbx5 at the apex of the sinoatrial node (SAN) transcriptional program. To understand its role in SAN differentiation, clonal embryonic stem (ES) cell lines were made that conditionally overexpress Tbx5, Tbx3, Tbx18, Shox2, Islet-1, and MAP3k7/TAK1. Cardiac cells differentiated using embryoid bodies (EBs).

The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study.

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP).

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder.

Background: Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD.

Methods: We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3-12 years, with ASD over 36 weeks.

TAK1/Map3k7 enhances differentiation of cardiogenic endoderm from mouse embryonic stem cells.

Specification of the primary heart field in mouse embryos requires signaling from the anterior visceral endoderm (AVE). The nature of these signals is not known. We hypothesized that the TGFβ-activated kinase (TAK1/Map3k7) may act as a cardiogenic factor, based on its expression in heart-inducing endoderm and its requirement for cardiac differentiation of p19 cells.

Nkx2-5 Second Heart Field Target Gene Ccdc117 Regulates DNA Metabolism and Proliferation.

The cardiac transcription factor Nkx2-5 is essential for normal outflow tract (OFT) and right ventricle (RV) development. Nkx2-5 null mouse embryos display severe OFT and RV hypoplasia and a single ventricle phenotype due to decreased proliferation of Second Heart Field (SHF) cells, a pool of cardiac progenitors present in anterior pharyngeal arch mesoderm at mid-gestation. However, definition of the precise role of Nkx2-5 in facilitating SHF expansion is incomplete.

Overexpression of Map3k7 activates sinoatrial node-like differentiation in mouse ES-derived cardiomyocytes.

In vivo, cardiomyocytes comprise a heterogeneous population of contractile cells defined by unique electrophysiologies, molecular markers and morphologies. The mechanisms directing myocardial cells to specific sub-lineages remain poorly understood. Here we report that overexpression of TGFβ-Activated Kinase (TAK1/Map3k7) in mouse embryonic stem (ES) cells faithfully directs myocardial differentiation of embryoid body (EB)-derived cardiac cells toward the sinoatrial node (SAN) lineage.

Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders.

Objective: An imbalance of excitatory and inhibitory neurotransmission in autism spectrum disorder (ASD) has been proposed. We compared glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) of 13 males with ASD and 14 typically developing (TD) males (ages 13-17), and correlated these levels with intelligence quotient (IQ) and measures of social cognition.

Methods: Social cognition was evaluated by administration of the Social Responsiveness Scale (SRS) and the Reading the Mind in the Eyes Test (RMET).

Tissue engineering approaches to heart repair.

The heart is a large organ containing many cell types, each of which is necessary for normal function. Because of this, cardiac regenerative medicine presents many unique challenges. Because each of the many types of cells within the heart has unique physiological and electrophysiological characteristics, donor cells must be well matched to the area of the heart into which they are grafted to avoid mechanical dysfunction or arrhythmia.

Gutsy moves in mice: cellular and molecular dynamics of endoderm morphogenesis.

Despite the importance of the gut and its accessory organs, our understanding of early endoderm development is still incomplete. Traditionally, endoderm has been difficult to study because of its small size and relative fragility. However, recent advances in live cell imaging technologies have dramatically expanded our understanding of this tissue, adding a new appreciation for the complex molecular and morphogenetic processes that mediate gut formation.

Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia.

Objective: Preeclampsia (PE) affects 2-8% of pregnancies worldwide and is a significant source of maternal and neonatal morbidity and mortality. However, the mechanisms underlying PE are poorly understood and major questions regarding etiology and risk factors remain to be addressed. Our objective was to examine whether abnormal expression of the cardiovascular developmental transcription factor, Nkx2-5, was associated with early onset and severe preeclampsia (EOSPE).

Nodal mutant eXtraembryonic ENdoderm (XEN) stem cells upregulate markers for the anterior visceral endoderm and impact the timing of cardiac differentiation in mouse embryoid bodies.

Interactions between the endoderm and mesoderm that mediate myocardial induction are difficult to study in vivo because of the small size of mammalian embryos at relevant stages. However, we and others have demonstrated that signals from endodermal cell lines can influence myocardial differentiation from both mouse and human embryoid bodies (EBs), and because of this, assays that utilize embryonic stem (ES) cells and endodermal cell lines provide excellent in vitro models to study early cardiac differentiation. Extraembryonic endoderm (XEN) stem cells have a particular advantage over other heart-inducing cell lines in that they can easily be derived from both wild type and mutant mouse blastocysts.

Diversification and conservation of the extraembryonic tissues in mediating nutrient uptake during amniote development.

The transfer of nutrients from the mother through the chorioallantoic placenta meets the nutritional needs of the embryo during human prenatal development. Although all amniotes start with a similar "tool kit" of extraembryonic tissues, an enormous diversity of extraembryonic tissue formation has evolved to accommodate embryological and physiological constraints unique to their developmental programs. A comparative knowledge of these extraembryonic tissues and their role in nutrient uptake during development is required to fully appreciate the adaptive changes in placental mammals.

eXtraembryonic ENdoderm (XEN) stem cells produce factors that activate heart formation.

Background: Initial specification of cardiomyocytes in the mouse results from interactions between the extraembryonic anterior visceral endoderm (AVE) and the nascent mesoderm. However the mechanism by which AVE activates cardiogenesis is not well understood, and the identity of specific cardiogenic factors in the endoderm remains elusive. Most mammalian studies of the cardiogenic potential of the endoderm have relied on the use of cell lines that are similar to the heart-inducing AVE.

Cardiac lineage selection: integrating biological complexity into computational models.

The emergence of techniques to study developmental processes using systems biology approaches offers exciting possibilities for the developmental biologist. In particular cardiac lineage selection may be particularly amenable to these types of studies since the heart is the first fully functional organ to form in vertebrates. However there are many technical obstacles that need to be overcome for these studies to proceed.

Signaling pathways in early cardiac development.

Cardiomyocyte differentiation is a complex multistep process requiring the proper temporal and spatial integration of multiple signaling pathways. Previous embryological and genetic studies have identified a number of signaling pathways that are critical to mediate the initial formation of the mesoderm and its allocation to the cardiomyocyte lineage. It has become clear that some of these signaling networks work autonomously, in differentiating myocardial cells whereas others work non-autonomously, in neighboring tissues, to regulate cardiac differentiation indirectly.

A comparative analysis of extra-embryonic endoderm cell lines.

Prior to gastrulation in the mouse, all endodermal cells arise from the primitive endoderm of the blastocyst stage embryo. Primitive endoderm and its derivatives are generally referred to as extra-embryonic endoderm (ExEn) because the majority of these cells contribute to extra-embryonic lineages encompassing the visceral endoderm (VE) and the parietal endoderm (PE). During gastrulation, the definitive endoderm (DE) forms by ingression of cells from the epiblast.

Embryonic heart induction.

We have characterized two signaling pathways that induce heart tissue during embryonic development. The first is initiated by the Wnt antagonist Dickkopf1 (Dkk1) and involves the homeodomain transcription factor Hex. Other Wnt antagonists are less effective and the potency of Dkk1 might be due to synergy between Wnt antagonizing and another, novel activity emanating from its amino terminal cysteine-rich domain.

Multiple functions of Cerberus cooperate to induce heart downstream of Nodal.

The TGFbeta family member Nodal has been implicated in heart induction through misexpression of a dominant negative version of the type I Nodal receptor (Alk4) and targeted deletion of the co-receptor Cripto in murine ESCs and mouse embryos; however, whether Nodal acts directly or indirectly to induce heart tissue or interacts with other signaling molecules or pathways remained unclear. Here we present Xenopus embryological studies demonstrating an unforeseen role for the DAN family protein Cerberus within presumptive foregut endoderm as essential for differentiation of cardiac mesoderm in response to Nodal. Ectopic activation of Nodal signaling in non-cardiogenic ventroposterior mesendoderm, either by misexpression of the Nodal homologue XNr1 together with Cripto or by a constitutively active Alk4 (caAlk4), induced both cardiac markers and Cerberus.

Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex.

Inhibition of canonical Wnt/beta-catenin signaling by Dickkopf-1 (Dkk-1) or Crescent initiates cardiogenesis in vertebrate embryos. However, nearly nothing is known about the downstream effectors of these secreted Wnt antagonists or the mechanism by which they activate heart formation. Here we show that Wnt antagonists in Xenopus stimulate cardiogenesis non-cell-autonomously, up to several cells away from those in which canonical Wnt/beta-catenin signaling is blocked, indicative of an indirect role in heart induction.

Heart induction: embryology to cardiomyocyte regeneration.

Developmental biologists have uncovered many of the signaling proteins that are required to recruit early embryonic cells to the myocardial lineage. A detailed understanding of their function should provide insights into the difficult task of inducing embryonic stem cells to develop cardiomyocyte precursors for cell-based therapies. These proteins may also prove to be useful to stimulate progenitor cells to differentiate into cardiomyocytes within the damaged heart.