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Red fish, blue fish, Brainbow fish!

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Woods Hole Images round 3 – vote for a Development cover

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Interview with the BSDB Poster winner Aditya Saxena

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Gone today, hair tomorrow? Changes in dermal papilla cell number drive hair thinning and loss.

In Development This Week (Vol. 138, Issue 22)

Posted by on October 25th, 2011

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Here are the highlights from the current issue of Development:

The skin-healing touch of Lhx2


Skin repair after injury involves the recruitment of undifferentiated progenitor cells from nearby hair follicles (HFs) into the regenerating epidermis. The bulge and the secondary hair germ of HFs contain distinct populations of epithelial stem cells, and now Vladimir Botchkarev and co-workers reveal that the Lim-homeodomain transcription factor Lhx2 differentially regulates these populations during wound healing (p. 4843). They show that, in mice, most of the cells that proliferate in response to skin injury in the HF bulge and secondary hair germ express Lhx2. Wound re-epithelisation is retarded in Lhx2+/– mice compared with wild-type mice, they report, whereas the onset of active hair growth in HFs near to the wound is accelerated. Other experiments indicate that Lhx2 promotes wound re-epithelisation by upregulating Sox9 and Tcf4 expression in the bulge cells while simultaneously inhibiting HF cycling by downregulating Lgr5 expression in the secondary hair germ. Thus, Lhx2 is a key regulator of the differential response of HF stem cells during epidermal regeneration after injury.



Nanog: an ancient reprogrammer


The establishment of pluripotency during mouse embryogenesis and during the reprogramming of somatic cells is dependent on the homeodomain-containing transcription factor Nanog but, puzzlingly, compared with other pluripotency-associated genes, Nanog is poorly conserved among vertebrates. Here (p. 4853), José Silva, Filipe Castro and colleagues investigate whether Nanog orthologues can orchestrate pluripotency in Nanog–/– mouse somatic cells. Surprisingly, the researchers report that mammalian, avian and teleost Nanog orthologues all reprogramme mouse Nanog-/- somatic cells to full pluripotency, despite sharing as little as 13% sequence identity with mouse Nanog. Moreover, they identify two unique residues in the DNA recognition helix of the Nanog homeodomain that are important for reprogramming and show that the Nanog homeodomain is sufficient to enable naive pluripotency in Nanog–/– somatic cells. These functional studies, together with genome analyses, suggest that Nanog is a vertebrate innovation and that its reprogramming capacity resides within a unique DNA-binding domain that probably appeared at least 450 million years ago in a common ancestor of vertebrates.



R-spondin to developmental angiogenesis


During embryogenesis, two sequential processes form the vasculature: during vasculogenesis, endothelial progenitor cells form the primary vascular bed; subsequently, during angiogenesis, additional vessels sprout and grow from pre-existing vessels. Here, Aniket Gore, Brant Weinstein and co-workers identify a novel signalling pathway that promotes developmental angiogenesis in zebrafish (see p. 4875). Their first clue to this pathway came when they identified a mutation in R-spondin1 (rspo1) during a forward-genetic screen for angiogenesis-deficient zebrafish mutants. Embryos lacking rspo1 or its receptor kremen form primary vessels, they report, but do not undergo angiogenesis. R-spondin is a Wnt signalling regulator and, by functionally manipulating different members of the Wnt pathway, the researchers show that canonical Wnt signalling is required downstream of rspo1 for sprouting angiogenesis. Finally, they show that Vegfc/Vegfr3 signalling mediates the pro-angiogenic effects of Rspo1/Wnt signalling and that all four proteins are expressed by the endothelium during sprouting angiogenesis. Together, these results suggest that Rspo1-Wnt-Vegfc-Vegfr3 signalling is an endothelial-autonomous permissive cue for developmental angiogenesis.



Compartmentalised PKA, cilia and hedgehog signalling


Protein kinase A (PKA), a conserved negative regulator of the hedgehog (Hh) signalling pathway, generates the transcriptional repressor form of Gli3 in the absence of Hh in mice. Now, Kathryn Anderson and colleagues show that the total loss of PKA activity in mouse embryos leads to a completely ventralised neural tube and mid-gestation lethality (see p. 4921), which indicates that the sonic hedgehog (Shh) signalling pathway is maximally activated in all neural progenitors in the absence of PKA. Notably, genetic experiments indicate that the principal function of PKA in the neural plate is to prevent Gli2 activation of Shh targets. Other experiments reveal that Hh pathway activation in PKA mutants depends on cilia, that PKA is localised at the basal body of primary cilia, and that Gli2 levels are increased at the tips of cilia of PKA-null cells. The researchers propose, therefore, that two separate cilia-associated compartments determine the accessibility of Gli proteins to PKA and thus the activity of the Shh pathway in vertebrates.



miR-124 notches up neural development


MicroRNAs (miRNAs) play crucial roles in development. miR-124, for example, is abundantly expressed in the mouse brain and is necessary for proper nervous system development, but how it drives neuronal differentiation is unclear. To remedy this lack of understanding, Robert Zeller and colleagues have comprehensively analysed miR-124 expression, function and target genes in the ascidian Ciona intestinalis (see p. 4943). They report that miR-124 interacts with several signalling pathways that are involved in nervous system development. In particular, they show that a feedback interaction between miR-124 and Notch signalling regulates the epidermal-peripheral nervous system (PNS) fate choice in tail midline cells. Thus, Notch signalling silences miR-124 in epidermal midline cells, whereas in PNS midline cells miR-124 silences Notch, Neuralized and the Ciona Hairy/Enhancer-of-Split genes. Moreover, miR-124 also shapes neuronal progenitor fields by downregulating non-neural genes including 50 Brachyury-regulated notochord genes and the muscle specifier Macho-1. Overall, these results indicate that miR-124 plays a multifaceted role in cell lineage specification during nervous system development.



Spotlight on adipogenesis


Adipose tissue (a specialised energy storage structure) is the only tissue that can change its mass substantially during adult life. It does this through changes in the size of its constituent cells (adipocytes) and through the de novo generation of cells. Unfortunately, given the obesity epidemic, adipocyte development in vivo is poorly understood but, here, Gou Young Koh and colleagues provide new insights into adipogenesis by analyzing the postnatal development of epididymal adipose tissue (EAT) in mice (p. 5027). They show that EAT is generated from non-adipose tissue during the first 14 postnatal days of development and that this non-adipose tissue is initially composed of multipotent progenitor cells (possibly including adipoblasts) that lack adipogenic differentiation capacity in vitro. By postnatal day 4, however, progenitor cells isolated from EAT can form adipocytes if they are provided with cell-to-matrix and cell-to-cell contacts. Finally, the researchers show that impaired angiogenesis in postnatal mice interferes with adipogenesis. Thus, they conclude, cues from cellular and matrix components, together with appropriate angiogenesis, are required for adipose tissue development.



Plus…



Evolutionary crossroads in developmental biology: amphioxus


As part of the Evolutionary Crossroads in Developmental Biology series, Bertrand and Escriva introduce amphioxus and discuss how studies of this model have informed us about the evolution of vertebrate traits.


See the Primer article on p. 4819


An interview with Ottoline Leyser


The Sainsbury Laboratory at the University of Cambridge is a new research institute that aims to achieve an integrated understanding of plant development. Its Associate Director is the new plant Editor of Development, Ottoline Leyser, who is also Professor of Plant Development at the University of Cambridge. We recently caught up with Professor Leyser and asked her about the Sainsbury Laboratory and about her own research interests.


See the Spotlight article on p. 4815

 

 

 
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In Development this week (Vol. 138, Issue 16)

Posted by on July 26th, 2011

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Here are the research highlights from the current issue of Development:

Pushing the nuclear envelope


Not all nuclei are regular spheres as is often shown in textbooks. For example, in Drosophila embryos, nuclei are initially spherical but they elongate and acquire an irregular lobulated morphology during cellularisation. These morphological changes coincide with transcriptional activation of the zygotic genome and reflect poorly understood changes in nuclear envelope (NE) mechanics. Here (see p. 3377), Thomas Lecuit and co-workers provide new insights into NE morphogenesis in early Drosophila embryos. Microtubule (MT) polymerisation events produce the forces necessary for NE dynamics, they report, and the large-scale NE deformations associated with lobulation require both a concentration of MT polymerisation in bundles that are organised by dynein and the presence of the farnesylated inner nuclear membrane protein Kugelkern. The researchers also show that MT-induced NE deformations control the dynamics of chromatin and its organisation at steady state. They suggest, therefore, that the mechanical regulation of chromatin dynamics by MT-induced NE fluctuations might be important for gene regulation in Drosophila embryos.



Many roads lead to stem cell renewal


Tissue maintenance relies on adult stem cells that both self-renew and produce differentiating progeny in specialised niches. But stem cells are not immortal, so how are lost stem cells replaced? On p. 3367, Rebecca Sheng and Erika Matunis use extended live imaging of the Drosophila testis niche to investigate this question. Germline stem cells (GSCs) in the Drosophila testis are attached to somatic hub cells and divide asymmetrically to produce a stem cell that remains attached to the hub and a daughter cell that is displaced away from the hub. Unexpectedly, Sheng and Matunis show that ‘symmetric renewal’, a process in which GSC daughter cell pairs swivel so that both cells contact the hub, generates new GSCs in the testis niche. Moreover, after severe genetically induced GSC loss, the rate of symmetric renewal increases and, in addition, spermatogonia de-differentiate. Thus, asymmetric stem cell divisions do not always lead to an asymmetric cell fate, and lost stem cells can be regenerated by multiple mechanisms.



CaMK-II: the missing link in kidney development


Ca2+ signalling influences many processes during early development, including organogenesis, but the pathways through which intracellular Ca2+ acts remain elusive. On p. 3387, Rob Tombes and colleagues show that, during pronephric kidney development in zebrafish, the conserved calmodulin-dependent protein kinase CaMK-II is an effector of the Ca2+ channel PKD2 (a polycystin that is mutated in the ciliopathy autosomal dominant polycystic kidney disease, ADPKD). The researchers show that activated CaMK-II is present during early zebrafish development in the pronephric kidney and in other ciliated tissues. Pronephric duct formation fails in both PKD2-deficient and CaMK-II-deficient embryos, they report, and both types of embryo develop kidney cysts and have destabilised cloacal cilia. Importantly, PKD2 suppression inactivates CaMK-II in pronephric cells and cilia, whereas constitutively active CaMK-II restores pronephric duct formation in PKD2-deficient embryos. The researchers conclude that CaMK-II is a crucial PKD2 target that promotes pronephric kidney development and stabilises primary cloacal cilia, and suggest that CaMK-II could provide a therapeutic target for ADPKD and other ciliopathies.



Hear, hear: Kif3a and auditory hair cell polarisation


In the mammalian cochlea, V-shaped hair bundles (rows of actin-based stereocilia) on sensory hair cells convert sound energy into electrical signals. The hair cells display uniform planar polarity, which is necessary for correct sound perception and is controlled by non-canonical Wnt/planar cell polarity (PCP) signalling at the tissue level. But how is the V-shape of hair bundles established? On p. 3441, Conor Sipe and Xiaowei Lu report that the microtubule motor subunit Kif3a regulates hair cell planar polarisation in mice through both ciliary and non-ciliary mechanisms. They show that Kif3a disruption in the inner ear leads to the absence of the kinocilium (a specialised primary cilium), flattened hair bundle morphology and uncoupling of hair bundle orientation from basal body positioning. Moreover, they report, Kif3a coordinates the planar polarity of hair bundles and hair cell centrioles through localised p21-activated kinase (PAK) activation on the hair cell cortex. These results suggest that Kif3-mediated hair cell intrinsic polarity pathways and PCP signalling converge on PAK to regulate hair cell polarity.



Fishing for ways to mend broken hearts


In heart failure, which is characterised by exercise intolerance, shortness of breath and oedema, the heart muscle is unable to pump a sufficient blood supply around the body. Cardiac muscle regeneration might thus restore function to a failing heart but how can cardiomyocyte regeneration be achieved? A zebrafish model of cardiac injury developed by Kenneth Poss and colleagues (see p. 3421) could provide valuable clues. It is known that adult zebrafish can regenerate cardiac muscle after surgical removal of about 20% of the ventricle. To study heart regeneration after larger injuries, the researchers created transgenic zebrafish in which destruction of more than 60% of the ventricular myocardium can be genetically induced. This massive myocardial loss triggers exercise intolerance in the fish, they report, but is completely reversed within 30 days through de-differentiation and proliferation of surviving cardiomyocytes. This new model of heart injury can now be used to understand why heart regeneration occurs in zebrafish – information that might help efforts to reverse human heart failure.



INCENP goes to seed


In plants, gametes and the accessory cells that support them are formed from haploid gametophytes during a tightly regulated developmental program that involves cell division, cell specification and cell differentiation. Now, on p. 3409, Ueli Grossniklaus and colleagues report that WYRD (WYR), which encodes a putative plant ortholog of the inner centromere protein (INCENP, a protein that controls chromosome segregation and cytokinesis in yeasts and animals), is required for cell specification in the female gametophyte and for seed development in Arabidopsis. The wyr mutant, which was identified in a screen for mutations affecting egg cell differentiation, produces additional egg cells at the expense of accessory cells. Disruption of WYR, the researchers report, also affects mitotic divisions in the male gametophyte (pollen) and the endosperm, and has a parental effect on embryo cytokinesis, which suggests that WYR is involved in cell-cycle regulation. Finally, WYR expression is upregulated in gametic cells. Together, these results reveal a new developmental function for the conserved cell-cycle-associated INCENP protein in plant reproduction.



Plus…



The mammalian target of rapamycin (mTOR) responds to an array of signals to regulate cell metabolism and growth. Recent studies, reviewed by Guan and colleagues, highlight a role for mTOR signaling in metabolically sensitive tissues and in stem cells.
See the Review article on p. 3343.


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In Development this week (Vol. 138, Issue 6)

Posted by on February 22nd, 2011

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Here are the research highlights from the current issue of Development:

Arteriovenous-specific regulation of angiogenesis


Endothelial cells (ECs) assume arterial- or venous-specific molecular characteristics at early stages of development. These lineage-specific molecular programmes subsequently instruct the development of the distinct vascular architectures of arteries and veins. Now, on p. 1173, Jau-Nian Chen and co-workers investigate the role that these early molecular programmes play in angiogenesis. Using the zebrafish caudal vein plexus as a model for venous-specific angiogenesis, they identify a new compound, aplexone, as an inhibitor of venous, but not arterial, angiogenesis. They show that aplexone targets the HMG-CoA reductase (HMGCR) pathway and that injection of mevalonate, a metabolic product of HMGCR, into zebrafish embryos reverses the effect of aplexone on venous angiogenesis. They also show that the inhibitory effect of aplexone on venous angiogenesis in zebrafish and human ECs is mediated by HMGCR-regulated membrane targeting of the small GTPase RhoA through protein prenylation. These and other findings indicate that angiogenesis is differentially regulated by the HMGCR pathway in an arteriovenous-specific manner in both zebrafish and human ECs.



miRNA hits Barx1 in the stomach


The spatiotemporal control of gene expression is crucially important during development, and microRNAs (miRNAs; short RNA molecules that silence complementary mRNA sequences) are thought to fine-tune the expression of developmentally important genes. Here, Ramesh Shivdasani and colleagues report that specific miRNAs influence mouse stomach organogenesis by regulating the expression of the mesenchymal transcription factor Barx1 (see p. 1081). Barx1 controls stomach morphogenesis and helps to specify the stomach-specific epithelium. However, Barx1 levels in the stomach decline sharply after epithelial specification. The researchers show that depletion of the miRNA-processing enzyme Dicer in cultured stomach mesenchymal cells increases Barx1 levels and that conditional Dicer gene deletion in mice disrupts stomach development. They identify miR-7a and miR-203 as regulators of Barx1 expression and show that these miRNAs repress Barx1 expression in the developing stomach by binding to the Barx1 3′ untranslated region. Barx1 downregulation by miRNAs in the mouse embryonic stomach might thus be an example of a widely used mechanism for modulating gene expression during development.



EGF signals muscle in to maintain intestinal stem cells


In high-turnover tissues, the precise control of stem cell proliferation is essential for tissue homeostasis. In Drosophila, the integrity of the midgut epithelium is maintained by intestinal stem cells (ISCs) but what regulates the proliferation of these cells? Benoît Biteau and Heinrich Jasper now report that EGF receptor (EGFR) signalling maintains the proliferative capacity of ISCs (see p. 1045). Using clonal analysis, RNAi knockdown and other experimental approaches, the researchers show that the EGF ligand Vein is expressed in the muscle surrounding the intestinal epithelium and that Vein provides a constitutive signal that activates ERK (extracellular signal-regulated kinase) in ISCs. Interestingly, the transcription factor FOS integrates this EGFR/ERK signal with signals mediated by the JNK (Jun N-terminal kinase) pathway in response to stress. The researchers suggest that the visceral muscle acts as a functional niche for ISCs and propose that FOS, by integrating the niche-derived permissive signal with stress-induced instructive signals, adjusts ISC proliferation to environmental conditions.



Niche-free progression of adult neural stem cells


Many tissues contain adult stem cells that could provide sources of cells for cell-based therapies. For example, adult neural stem cells (NSCs), which are found in brain regions such as the subependymal zone (SEZ), could be used to treat nervous system disorders. Little is known, however, about the intrinsic specification of adult NSCs or how dependent this specification is on the local niche. To understand the biology of NSCs better, Benedikt Berninger and co-workers have been using continuous live imaging to follow the cell divisions and lineage progression of cells isolated from the adult mouse SEZ (see p. 1057). They now report that SEZ cells cultured at low density without growth factors are primarily neurogenic, and that adult NSCs progress through stereotypic lineage trees consisting of asymmetric stem cell divisions, symmetric transit-amplifying divisions and final symmetric neurogenic divisions. The researchers conclude from these results that lineage progression from stem cell to neuron is cell-intrinsic and is independent of the local niche to a surprising degree.



Going with the flow: Pkd1l1 and Pkd2 set L-R axis


The internal organs of all vertebrates show distinct left-right (L-R) asymmetry. The earliest known event in the establishment of this asymmetry is a leftwards extracellular fluid flow at the embryonic node. This ‘nodal flow’, which is generated by the rotational movement of node cilia, activates asymmetric gene expression. But how is nodal flow detected? The two-cilia hypothesis proposes that, whereas motile cilia generate the flow, immobile node cilia detect nodal flow and respond by generating a left-sided Ca2+ signal. This signal generation is thought to be mediated by a complex consisting of the calcium channel polycystic kidney disease 2 (Pkd2) and an unknown sensor protein. In this issue, two papers further evaluate this hypothesis.


On p. 1131, Dominic Norris and colleagues identify the Pkd1-related locus Pkd1l1 as the missing Pkd2 partner and sensor protein in L-R patterning in mouse. Point mutants in either Pkd1l1 or Pkd2 fail to activate asymmetric gene expression at the node, they report, and develop similar L-R patterning defects. Cilia and node morphology and cilia motility are normal in both types of mutant, however, which suggests that Pkd1l1 and Pkd2 act downstream of nodal flow. Moreover, Pkd1l1 and Pkd2 localise to cilia and interact physically. Thus, the researchers propose, Pkd1l1 and Pkd2 form a cilia-specific stress-responsive channel in the node, a conclusion consistent with the two-cilia hypothesis.


On p. 1121, Hiroyuki Takeda and colleagues report that the medaka mutant abecobe is defective for L-R asymmetric gene expression but not for nodal flow, and identify the abecobe gene as Pkd1l1. They show that Pkd1l1 expression is confined to Kuppfer’s vesicle (KV; a medaka organ equivalent to the mouse node) and that, as in the mouse, Pkd1l1 interacts with and colocalises with Pkd2 in KV cilia. However, importantly, the researchers report that all KV cilia contain Pkd1l1 and Pkd2 and that all of the KV cilia are motile. These results necessitate reconsideration of the two-cilia model for L-R patterning and the researchers propose a new model in which cilia both generate nodal flow and interpret it through a nodal flow sensor that consists of Pkd1l1-Pkd2 complexes.



Plus…


Definitive hematopoietic stem cells (HSCs) give rise to all of the mature blood cell lineages in adults, and, as reviewed by Alexander Medvinsky and colleagues, recent advances have shed light on the embryonic origin of HSCs. See the Review Article on p. 1017



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In Development this week (Vol. 137, Issue 24)

Posted by on November 23rd, 2010

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Pak1-ing a punch in lumen formation


The generation and maintenance of correct lumen size and shape is essential for the function of tubular organs. Now, Monn Monn Myat and co-workers report that p21-activated kinase (Pak1) plays a novel role during lumen formation in Drosophila embryonic salivary glands (see p. 4177). The researchers show that Pak1 regulates the size and elongation of the apical domain of individual epithelial cells in the developing gland by decreasing and increasing E-cadherin levels at adherens junctions and basolateral membranes, respectively. Pak1 mediates these effects, they report, through Rab5- and Dynamin-dependent endocytosis of E-cadherin. Moreover, constitutively active Pak1 induces the formation of multiple intercellular lumens in the gland, an effect that is dependent on Rab5 and Dynamin, and on the Pak1 substrate Merlin. Together, these results identify a crucial role for Pak1 and E-cadherin endocytosis in lumen size and shape determination in fly salivary glands, and highlight a mechanism for multiple lumen formation, a process that occurs in pathological conditions such as breast ductal carcinoma in situ.



Shh signalling out-Foxed by cilia


Sonic hedgehog (Shh) signalling controls cellular differentiation in the neural tube by regulating a poorly defined gene regulatory network. To better understand this network, James Briscoe and colleagues have undertaken a genome-wide expression screen in chick neural tube and, on p. 4271, they identify the forkhead transcription factor Foxj1 as an Shh target gene in this tissue. Foxj1, they report, is expressed in the chick and mouse neural tube in cells that constitute the floor plate (FP), a neural tube organising centre. Foxj1 expression is associated with the formation of long motile cilia in several cell types and, consistent with this, the authors show that chick and mouse FP cells produce primary cilia longer than those produced elsewhere in the neural tube. Finally, they show that Foxj1 expression in the neural tube attenuates Shh signal transduction by altering cilia structure and modifying the intracellular localisation of the Gli proteins that mediate Shh signalling. Together, these data reveal a novel cilia-dependent mechanism that modulates cellular responses to Shh signalling.



Leaves send mobile signals for size


Organ size in plants and animals is tightly controlled, and partly determined, by cell size and number. Plant leaves, for example, exhibit compensation, in which defective cell proliferation triggers increased postmitotic cell expansion. Now, Hirokazu Tsukaya and colleagues (p. 4221) identify two novel pathways coordinating cell proliferation and expansion in Arabidopsis leaves. Two Arabidopsis mutants, the loss-of-function ANGUSTIFOLIA3 (AN3, a transcriptional co-activator) mutant and the overexpressor KIP-RELATED PROTEIN2 (KRP2, a cyclin-dependent kinase inhibitor) mutant show compensation: in an3 mutant leaves, cell numbers decrease by ~70%, whereas cell size increases by 50%. Using the Cre/lox system, the authors generated leaves chimeric for AN3 and KRP2 expression, and investigated whether compensation occurs in a cell-autonomous or non-cell-autonomous manner. An3-dependent compensation, they report, is indeed non-cell-autonomous and occurs via an intercellular signal restricted to one half of leaves. Conversely, compensation caused by KRP2 overexpression occurs cell-autonomously, possibly via a mitotic cell cycling defect. Future work should shed more light on these events and identify the transmitted signal.



Ongoing Phox2 locks in neuronal differentiation


During neuronal differentiation, expression of the transcription factors that determine neuronal identity often continues after their downstream genetic program has been launched. Is this continued expression required for neuronal differentiation? On p. 4211, Jean-François Brunet and colleagues address this question by inactivating the paired-like homeobox genes Phox2a and Phox2b, which specify several classes of visceral neurons, after the developmental timepoint at which they act to initiate visceral neuron differentiation. They report that ongoing Phox2b expression is required in branchiomotor and visceromotor neuronal precursors after their initial specification to maintain their molecular signature, migration pattern and cellular differentiation. Similarly, maintenance of noradrenergic neuron differentiation during embryogenesis requires the ongoing expression of Phox2b in sympathetic ganglia and of Phox2a in the main noradrenergic centre of the developing brain. Thus, neuronal differentiation does not always unfold as a transcriptional ‘cascade’ in which downstream events are irreversibly triggered by an upstream regulator. Instead, as seen here, it sometimes requires continuous input from so-called ‘terminal selector genes’.



Hippo links growth control to tissue homeostasis


Both tissue repair and tissue homeostasis require stem cells that proliferate to replenish lost cells, but the way in which adult stem cells respond to damage and switch between homeostatic and rapid proliferative states is not well understood. In the Drosophila midgut, intestinal stem cells (ISCs) maintain homeostasis, and, in response to damage, can proliferate rapidly following activation of the Jak/Stat pathway. In this issue, two papers demonstrate that Drosophila ISC proliferation, and hence intestinal regeneration, are regulated by the Hippo (Hpo) tumour suppressor pathway, providing an exciting new link between growth control and stem cell proliferation.


On p. 4147, Nicolas Tapon and colleagues examine the effects of Hpo pathway inactivation in the midgut by overexpressing Yorkie (Yki), a progrowth target that is usually repressed by the Hpo pathway. They report that Yki overexpression in differentiated cells increases ISC proliferation non-cell-autonomously without affecting differentiation, and induces the expression of the Jak/Stat pathway ligand Unpaired. The authors also observe that Yki target genes are induced by bacterial infection, and suggest that the Hpo pathway acts to sense cellular stress within the midgut. Finally, using RNAi, they show that Yki is also required within ISCs to drive proliferation in response to bacterial-induced tissue stress. Based on their findings, they propose that the Hpo pathway is a mediator of the Drosophila midgut regenerative response.


In a second, related paper, Norbert Perrimon and co-workers (p. 4135) demonstrate that Yki overexpression in ISCs induces proliferation cell-autonomously, whereas Yki loss has no effect on ISCs during normal homeostasis. They also show that Yki activity is required in ISCs to mediate the proliferative response to tissue damage, and propose that this effect is elicited by downstream targets that are involved in proliferation and survival. Importantly, they report that, prior to tissue damage, Yki is also repressed by the atypical cadherins Fat and Dachsous, which are upstream components of the Hpo pathway. From their findings, the researchers propose that Yki is inactive under normal homeostasis but becomes activated to induce ISC proliferation when cell-contact cues, and thus Hpo signal transduction, are disrupted by tissue injury.



Also…


Germline segregation in metazoans can occur during or after embryogenesis and often involves a common set of genes. Juliano, Swartz and Wessel now propose that this gene set represents a conserved germline multipotency programme operating in germ cells and multipotent progenitors.

See the Hypothesis article on p. 4113



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In Development this week (Volume 137, Issue 18)

Posted by on August 24th, 2010

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Non-muscle myosin II translates cilia polarity


In the brain, cilia on the multiciliated ependymal cells that line the brain ventricles circulate cerebrospinal fluid over the brain surface. To generate this directional fluid flow, the ependymal cell cilia and their basal bodies must be orientated in one direction. This ‘rotational’ polarity is regulated by the planar cell polarity (PCP) pathway. Recent reports have revealed that the basal bodies are also localised at the anterior of the ependymal cells but how is this ‘translational’ polarity established? Using a new method for time-lapse imaging of ventricular walls, Kazunobu Sawamoto and co-workers now show that, in mice, the anterior migration of basal bodies in the apical cell membrane during ependymal cell differentiation establishes translational polarity (see p. 3037). Inhibition of the PCP protein dishevelled 2, which disrupts rotational polarity, does not affect translational polarity, the researchers report. Instead, their pharmacological and genetic studies identify non-muscle myosin II as a key regulator of translational polarity. Thus, different mechanisms regulate the orientation and distribution of basal bodies in ependymal cells.



SNP links Dlx gene regulation to autism


Several neurodevelopmental disorders, including autism, have been linked to the aberrant development of γ-aminobutyric acid (GABA)-expressing interneurons in the mammalian forebrain. Dlx homeobox genes control the development of these interneurons and now, on p. 3089, Marc Ekker and colleagues report that a rare, autism-associated single-nucleotide polymorphism (SNP) in an ultraconserved regulatory element (I56i) in the DLX5/DLX6 bigene cluster affects Dlx5/Dlx6 regulation in the mouse forebrain. The researchers show that the SNP, which lies in a functional protein binding site, reduces I56i enhancer activity in the developing mouse forebrain and in adult GABAergic interneurons. Notably, Dlx proteins have a reduced affinity for the variant I56i protein binding site in vitro, they report, which reduces the transcriptional activation of the enhancer by Dlx. The researchers propose, therefore, that impaired I56i enhancer activity by the SNP could affect the auto- or cross-regulation of the DLX5/DLX6 bigene cluster, thereby disrupting cortical interneuron development and contributing to the developmental abnormalities that underlie autism.



Symmetric neural progenitor divisions Notch up


During development, the balance between neural stem cell self-renewal and differentiation is carefully controlled to ensure that the correct number of neurons is produced to build functional neural networks. In the Drosophila optic lobe, as in the mammalian cerebral cortex, neuroepithelial (NE) cells initially divide symmetrically to expand the stem cell pool, before switching to asymmetric division to generate neurons. Andrea Brand and colleagues now report that Notch regulates this important cell fate transition (see p. 2981). By comparing the transcriptomes of microdissected NE cells and neuroblasts, the researchers show that Notch signalling pathway members are preferentially expressed in NE cells. Notch mutant cells are extruded from the neuroepithelium and undergo premature neurogenesis, they report. Furthermore, a wave of proneural gene expression transiently represses Notch activity in NE cells to enable the transition from symmetrically dividing NE cell to asymmetrically dividing neuroblast. This progression resembles that seen in the vertebrate cerebral cortex, leading the researchers to propose that neurogenesis regulation could be conserved between these two systems.



Changing identities: neuronal transdifferentiation


Traditionally, cellular differentiation is thought to be an irreversible commitment to a given cell identity. So, for example, differentiated neurons cannot generate new cells or adopt new identities. Now, however, Melissa Wright and colleagues provide evidence for the transdifferentiation of dorsal root ganglia (DRG) sensory neurons in zebrafish larvae (see p. 3047). Using time-lapse microscopy, the researchers track DRG neurons in wild-type zebrafish and in zebrafish mutant for the nav1.6 voltage-gated sodium channel. Some DRG neurons migrate ventrally from their normal position and then adopt a phenotype characteristic of sympathetic neurons in both types of larvae, they report, but more DRG neurons transdifferentiate in the mutant larvae. Furthermore, although the loss of sodium channel expression promotes the migration of DRG neurons, once in a new environment, these neurons transdifferentiate regardless of sodium channel expression. Thus, the researchers conclude, differentiated sensory neurons retain the plasticity needed to transdifferentiate when challenged by a new environment, a finding that suggests new strategies for the treatment of nervous system diseases.



Heartfelt responses to opposing FGF/BMP signals


Congenital heart disease – the commonest type of human birth defect – is the result of abnormal early heart development. In this issue, two papers investigate how opposing fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signals control the differentiation of the secondary heart field (SHF) and anterior heart field (AHF) cardiac progenitors during early vertebrate heart development.
On p. 3001, by isolating and culturing chick SHF mesoderm, which forms the myocardium and smooth muscle of the heart’s arterial pole (the outflow region of the heart), Mary Hutson and colleagues show that this tissue contains stem cells that can differentiate into myocardium, smooth muscle and endothelial cells. By treating SHF (arterial pole) progenitor cultures with combinations of growth factors and inhibitors, the researchers show that BMP promotes myocardial differentiation but not proliferation of the arterial pole progenitors, whereas FGF promotes their proliferation and smooth muscle cell differentiation but inhibits myocardial differentiation. These and other results indicate that myocardial differentiation of the SHF progenitors requires BMP signalling and downregulation of the FGF/ERK pathway and suggest that the FGF pathway maintains the SHF stem cell pool early but promotes smooth muscle cell differentiation later.


On p. 2989,, Eldad Tzahor and colleagues provide further insights into how opposing BMP and FGF signals regulate cardiogenesis by studying the differentiation of chick AHF progenitors, which contribute to the right ventricle and to the arterial pole. By perturbing signalling pathways in vitro and in vivo, the researchers show that, as in SHF progenitors, BMP promotes myocardial differentiation of AHF progenitors by blocking FGF/ERK signalling and that FGF signalling prevents their premature myocardial differentiation. They also show that BMP4 induces the expression of several neural crest-related genes and that cranial neural crest cells are required for BMP-dependent myocardial differentiation of the AHF progenitors. Thus, Tzahor and colleagues suggest, BMP and FGF signalling pathways coordinate the balance between the proliferation and differentiation of cardiac progenitors in the AHF through regulatory loops that act in multiple tissues.

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