Mammalian Patterning Research Articles

The dynamics of morphogenesis in stem cell-based embryology: Novel insights for symmetry breaking

Breaking embryonic symmetry is an essential prerequisite to shape the initially symmetric embryo into a highly organized body plan that serves as the blueprint of the adult organism. This critical process is driven by morphogen signaling gradients that instruct anteroposterior axis specification. Despite its fundamental importance, what triggers symmetry breaking and how the signaling gradients are established in time and space in the mammalian embryo remain largely unknown. Stem cell-based in vitro models of embryogenesis offer an unprecedented opportunity to quantitatively dissect the multiple physical and molecular processes that shape the mammalian embryo. Here we review biochemical mechanisms governing early mammalian patterning in vivo and highlight recent advances to recreate this in vitro using stem cells. We discuss how the novel insights from these model systems extend previously proposed concepts to illuminate the extent to which embryonic cells have the intrinsic capability to generate specific, reproducible patterns during embryogenesis.

A chronological expression profile of gene activity during embryonic mouse brain development

The brain is a functionally complex organ, the patterning and development of which are key to adult health. To help elucidate the genetic networks underlying mammalian brain patterning, we conducted detailed transcriptional profiling during embryonic development of the mouse brain. A total of 2,400 genes were identified as showing differential expression between three developmental stages. Analysis of the data identified nine gene clusters to demonstrate analogous expression profiles. A significant group of novel genes of as yet undiscovered biological function were detected as being potentially relevant to brain development and function, in addition to genes that have previously identified roles in the brain. Furthermore, analysis for genes that display asymmetric expression between the left and right brain hemispheres during development revealed 35 genes as putatively asymmetric from a combined data set. Our data constitute a valuable new resource for neuroscience and neurodevelopment, exposing possible functional associations between genes, including novel loci, and encouraging their further investigation in human neurological and behavioural disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-013-9486-7) contains supplementary material, which is available to authorized users.

140. THE DEVELOPMENT OF THE PHALLUS IN A MARSUPIAL

The phallus, the limbs and the tail are all considered appendages in the developing mammal. In mice, several key genes including FGF8, BMP4, SHH, DLX5 and DLX6 are known to control the precise pattering of the limb and phallus in the fetus (reviewed in Yamada et al. 2006). The signalling cascade in both appendages begins with SHH interacting with FGF8. In humans, disruptions to these gene pathways result in malformations of both limbs and phallus because these appendages share conserved elements in patterning and development (Yamada et al. 2003). However, this is a poorly researched area so additional models are needed to provide a greater perspective into mammalian embryonic patterning especially of the external genitalia. In marsupials, since most sexual differentiation occurs after birth, the developing phallus and limbs are accessible at stages that occur in utero in humans and other eutherian mammals. We have used the tammar as an alternative model to understand the differentiation of the phallus and limb. FGF8, SHH and megalin mRNA and protein are all expressedin the limb and phallus from the early embryo until post-natal stages. SHH and megalin were co-localised in the urethral epithelium of the tammar phallus. This is the first study to detect megalin in the developing mammalian phallus. SHH is a critical gene in patterning the appendages, and megalin is a transport protein that ferries steroids into the cell where they can bind to their cognate receptor. It has a high affinity for the potent androgen androstanediol, an androgen critical for virilisation of the tammar phallus (Leihy et al. 2004). Further examination is underway to confirm whether the expression of the genes patterning the phallus in the mouse are conserved in the marsupial and whether megalin plays any role in the patterning of the phallus, possibly mediated by SHH.

Zic1 and Zic4 are required for mammalian cerebellar patterning and growth

Zic1 and Zic4 are required for mammalian cerebellar patterning and growth

How to Build Transcriptional Network Models of Mammalian Pattern Formation

BackgroundGenetic regulatory networks of sequence specific transcription factors underlie pattern formation in multicellular organisms. Deciphering and representing the mammalian networks is a central problem in development, neurobiology, and regenerative medicine. Transcriptional networks specify intermingled embryonic cell populations during pattern formation in the vertebrate neural tube. Each embryonic population gives rise to a distinct type of adult neuron. The homeodomain transcription factor Lbx1 is expressed in five such populations and loss of Lbx1 leads to distinct respecifications in each of the five populations.Methodology/Principal FindingsWe have purified normal and respecified pools of these five populations from embryos bearing one or two copies of the null Lbx1GFP allele, respectively. Microarrays were used to show that expression levels of 8% of all transcription factor genes were altered in the respecified pool. These transcription factor genes constitute 20–30% of the active nodes of the transcriptional network that governs neural tube patterning. Half of the 141 regulated nodes were located in the top 150 clusters of ultraconserved non-coding regions. Generally, Lbx1 repressed genes that have expression patterns outside of the Lbx1-expressing domain and activated genes that have expression patterns inside the Lbx1-expressing domain.Conclusions/SignificanceConstraining epistasis analysis of Lbx1 to only those cells that normally express Lbx1 allowed unprecedented sensitivity in identifying Lbx1 network interactions and allowed the interactions to be assigned to a specific set of cell populations. We call this method ANCEA, or active node constrained epistasis analysis, and think that it will be generally useful in discovering and assigning network interactions to specific populations. We discuss how ANCEA, coupled with population partitioning analysis, can greatly facilitate the systematic dissection of transcriptional networks that underlie mammalian patterning.

BMP and nodal signaling act synergistically in mammalian rostral patterning

BMP and nodal signaling act synergistically in mammalian rostral patterning

Cilia/IFT in mammalian limb patterning

Cilia/IFT in mammalian limb patterning