Association between social relationship of mentors and depressive symptoms in first-time mothers during the transition from pregnancy to 6-months postpartum.

BACKGROUND: First-time motherhood is characterized by high psychosocial distress, which untreated, has serious consequences. Informal social support provided by specially trained mentors may be protective against postpartum depressive symptoms but may vary by women's social relationship with the mentor. The objective of this study was to evaluate the association of types of mentors on women's depressive symptoms between late pregnancy to 6-months postpartum and the characteristics of women associated with mentor type. METHODS: This study was a secondary analysis of data from a community sample of 312 primiparous women from a single-group, longitudinal intervention study of Welcome to Parenthood. Welcome to Parenthood provided education and mentorship for women during the transition from pregnancy to postpartum. Women completed the Edinburgh Postnatal Depression Scale (EPDS) in late pregnancy, and 2- and 6-months postpartum. RESULTS: Women who recently relocated were less likely to be mentored by their mothers and more likely to be mentored by friends or volunteers. Women who were mentored by their mothers or sisters scored the lowest on the EPDS; those mentored by their mothers-in-law scored the highest. Women who were mentored by other family, friends, or volunteers scored between the two extremes. EPDS scores of women mentored by each type of mentor decreased from pregnancy to 6-months postpartum; only for mother-, sister-, and volunteer-mentored groups was this decrease significant. CONCLUSIONS: During transition to parenthood, support provided by mothers or sisters is best for women's mental health but may not always be available to women who have recently relocated. In such situations, specially trained community volunteers may be the second-best option.

Welcome to Parenthood is associated with reduction of postnatal depressive symptoms during the transition from pregnancy to 6 months postpartum in a community sample: a longitudinal evaluation.

Becoming a mother is a fundamental life-transforming event characterized by high psychosocial distress. Most prenatal programming leaves women feeling unprepared for the realities of early parenthood. The purpose of this study was to design, implement, and evaluate a brief enhancement to existing prenatal programming, Welcome to Parenthood® (W2P). Using a single-group, longitudinal design, we implemented W2P with a community sample of 454 primiparous women via 11 Parent Link Centres in Alberta, Canada. The women completed questionnaires during late pregnancy, and 2 and 6 months postpartum to capture adverse childhood experiences (ACE), depressive symptoms (Edinburgh Postpartum Depression Scale; EPDS), and infant development (Ages and Stages Questionnaires; ASQs). Outcomes were compared with the naturalistic values from All Our Families community cohort from the same province and to the ASQ reference samples. By the end of W2P, depressive symptoms decreased significantly (p < .0001). The number of women with high depressive symptoms (EPDS ≥ 10) decreased almost by half, from 80 (17.6%) at enrollment to 41 (9.0%) at 6 months postpartum. Women with higher ACE had the greatest decrease in depressive symptoms. Infants in W2P had significantly better development than infants in reference samples. W2P is associated with improved maternal mood and infant development. Given that W2P is brief and uses natural supports, it may be integrated into existing prenatal programming for first-time mothers.

Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth.

Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth.

The transcriptional co-repressor TLE3 regulates development of trophoblast giant cells lining maternal blood spaces in the mouse placenta.

TLE3 is a transcriptional co-repressor that interacts with several DNA-binding repressors, including downstream effectors of the Notch signaling pathway. We generated Tle3-deficient mice and found that they die in utero and their death is associated with abnormal development of the placenta with major defects in the maternal vasculature. In the normal placenta, maternal blood spaces are lined, not as usual in the mammalian circulation by endothelial cells, but rather by specialized embryo-derived cells of the trophoblast cell lineage named trophoblast giant cells (TGC). Tle3 mRNA is expressed in those specialized TGC and Tle3 mutants show severe defects in differentiation of TGC-lined channels and lacunar spaces that take blood out of the labyrinth zone of the placenta and into the uterine veins. The mutants also show somewhat milder defects on the arterial-side of the maternal vascular circuit in spiral arteries and canals that take blood into the labyrinth. Notch2 and Tle3 expression patterns overlap in several TGC subtypes and we found that Tle3 and Notch2 mutants have some overlapping features. However, they also show differences implying that TLE3 may mediate some but not all of the effects of Notch2 signaling during placenta development. Therefore, formation of the different types of maternal blood spaces by different TGC subtypes is regulated by distinct molecular mechanisms.

Spatiotemporal expression of Notch receptors and ligands in developing mouse placenta.

Notch signaling is involved in cell lineage specification in many developing organs. In mice there are four known Notch receptor genes (Notch1-4) and five ligands genes (Dll1, 3, 4 and Jagged1 and 2). Notch2 is essential for development of placenta, an organ that mediates feto-maternal nutrient and gas exchange as well as maternal adaptations to pregnancy. However the role of other Notch receptors and ligands in placentation is not known. In order to gain better insight into the role of Notch signaling in mouse placenta we thoroughly analyzed mRNA expression of all Notch receptors and ligands in all trophoblast cell types from the embryonic day (E) 7.5 to E12.5, the period during which all of the substructures of the placenta develop. Here we show that Notch receptors and ligands are specifically and dynamically expressed in multiple cell layers of developing placenta. We found that the Notch2 receptor and Jagged1 and Jagged2 ligand genes are complementarily expressed in trophoblast cells of the chorion and its later derivatives in the labyrinth. Dll4 and Notch2 expression complement each other in the ectoplacental cone, while Dll1 and Notch2 are expressed in an ectoplacental cone derivative, the junctional zone. Moreover Dll4 and Notch2 are expressed at the ectoplacental cone-decidua interface at early stages of placentation. Additionally we show that Notch2 is dynamically expressed in all trophoblast giant cell subtypes, which is consistent with previous reports. Overall these expression pattern results suggest that Notch signaling may play several diverse roles during placenta development.

The expression of NOTCH2, HES1 and SOX9 during mouse retinal development.

Notch signaling is an important regulator of both developmental and post-developmental processes. In the developing retina, Notch1 is required for the maintenance of retinal progenitor cells and for inhibiting photoreceptor cell fate, while Notch3 is required for inhibiting ganglion cell fate. Here we used immunolabeling coupled with a knock-in reporter approach to obtain a detailed spatiotemporal expression pattern of Notch2 during mouse retinal development. Although previous in situ hybridization studies did not reveal appreciable levels of Notch2 in the developing retina, we detected NOTCH2 protein and reporter expression in early embryonic retinal progenitors that also expressed the Notch downstream gene, HES1. In the postnatal retina, NOTCH2, as well as the Notch downstream genes, HES1 and SOX9, were detected in VSX2/Cyclin D1/SOX2-expressing cells in the postnatal retina, and in the mature retina NOTCH2 was most abundant in Müller glia. Our findings indicate a potential role for Notch2 in the developing and mature retina.

The transcriptional co-repressor Grg3/Tle3 promotes pancreatic endocrine progenitor delamination and ß-cell differentiation.

Pancreatic ß-cells arise from Ngn3(+) endocrine progenitors within the trunk epithelium of the embryonic pancreas. The emergence of endocrine cells requires E-cadherin downregulation, but the crucial steps that elicit such are not clear, yet probably important for ultimately being able to efficiently generate ß-cells de novo from stem cells. Grg3 (groucho-related gene 3, also known as Tle3), encodes a member of the Groucho/TLE family of co-repressors and its function in various cell contexts is mediated by recruitment to target genes by different transcription factors. Grg proteins broadly regulate the progression of progenitor cells to differentiated cell types, but specific developmental mechanisms have not been clear. We find that Grg3 is expressed in most ß-cells and a subset of other endocrine cell types in the pancreas. Grg3 is highly expressed in Ngn3(+) endocrine progenitor descendants just after transient Ngn3 expression. Grg3-null embryos die at E14.5, which is associated with placental defects, so we explanted E12.5 pancreata to allow endocrine differentiation to occur in culture. Grg3 knockout explants displayed a drastic decrease in the differentiation of all endocrine cell types owing to defects in the delamination of early endocrine progenitors from the trunk epithelium. We find that Grg3 normally suppresses E-cadherin gene expression, thereby allowing delamination of endocrine cells from the trunk epithelium and revealing how this transcriptional co-repressor modulates this crucial step of ß-cell development.

A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia.

Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry, re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as they play important roles in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and expression of the arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion of Notch2, the only receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals by 30-40% and placental perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant offspring. In pre-eclampsia, expression of the Notch ligand JAG1 was absent in perivascular and endovascular TBs. We conclude that Notch signaling is crucial for TB vascular invasion.

Establishing three blastocyst lineages--then what?

Development of the mouse embryo to the blastocyst stage occurs over 3 to 4 days following fertilization of the oocyte. During this time, several molecular and morphological events take place that result in the formation of three distinct cell lineages: the trophectoderm, the epiblast, and the primitive endoderm. Many studies have investigated the processes that control lineage specification in the blastocyst including gene expression, cell signaling, cell-cell contact/positional relationships, and most recently, epigenetics. Here we review, at the molecular level, recent contributions to our understanding of the mechanisms that play a role in formation of these lineages. Additionally, we focus on the next steps in differentiation to highlight processes important in the development of those lineages that contribute to the extraembryonic tissues. In this context, we discuss the establishment of extraembryonic ectoderm and the contributions of parietal and visceral endoderm to yolk sac formation.

Mammalian Groucho homologs: redundancy or specificity?

The proteins termed TLE in humans, Grg in mice and Groucho in Drosophila constitute a family of transcriptional corepressors. In mammalians there are five different genes encoding an even larger number of proteins. Interactions between these TLE/Grg proteins and an array of transcription factors has been described. But is there any specificity? This review tries to make a case for a non-redundant function of individual TLE/Grg proteins. The specificity may be brought about by a tightly controlled temporo-spatial expression pattern, post-translational modifications, and subtle structural differences leading to distinct preferences for interacting transcription factors. A confirmation of this concept will ultimately need to come from genetic experiments.