Pattern formation and developmental mechanisms Converging views of diverging pathways Editorial overview Stuart K Kim* and Scott E Fraser-t Addresses *Department of Developmental Biology, 279 Campus Dr., Stanford Universtty, Medical Center, Stanford, California 94305.5329, USA; e-mail:
USA; e-mail: Current
http://biomednet.com/elecref/0959437X00300333 0 Current
developmental patterning In the last decade, these have been found to be pathways and regulatory
hierarchies. For example, anterior/posterior patterning in all animals are governed by the genes in the Hox cluster(s), and axis formation in the frog egg, limb development and pattern formation in insect wings are established by common signaling pathways. There has been great joy in discovering the unity in mechanisms for developmental patterning and there is also great power in knowing that similar types of genetic pathways regulate patterning in all animals. The underlying unity of developmental mechanisms has resulted in two basic approaches. The goal of the first basic approach is to obtain a deeper understanding of the fundamental mechanisms of development. Typically, model systems are chosen because they are simple and have very powerful experimental toolkits, allowing one to push back the frontier by identifying new components in genetic pathways, or by biochemically establishing how regulatory pathways work. In this issue, reviews by Jacobs and Shapiro (pp 386-391) and by Lu, Jan and Jan (pp 392-399) discuss good examples of microbe, fly uses to understand the fundamental rules asymmetric cell division.
theme in this issue biology has moved
is that the field beyond studying
pathway in a single cell pathways are relatively
of devela single
type or tissue. Many saturated in that a
continuous connection can be made from ligand to receptor to signal transducers and nuclear effecters. Reviews by Freeman (pp 407411) and by Rommel and Hafen (pp 412-418) on the Ras pathway, by Weinmaster (pp 436442) on the Notch pathway and by Cho and
One of the great themes in modern developmental biology is the underlying unity of developmental mechanisms that govern pattern formation in all animals. Superficially, many classical paradigms of appear to be quite different. classical experimental systems based upon similar signaling
worm and governing
The goal of the second basic approach is to apply known developmental themes to understand more and more complex patterning systems, ultimately leading to an understanding of human development and disease. The reviews by Schier and Talbot (pp 464-471) on the zebrafish organizer and by McGrew and Pourquit (pp 487493) on somitic patterning discuss good examples of understanding relatively complex patterning systems in vertebrates.
Blitz (pp 443449) on the BMP pathway discuss work in vvhich there is a continuous connection from extracellular signal to nuclear effector. Each of these reviews points out recent work focusing on how the fundamental problem of signaling specificity, which is how similar signaling pathways can result in diverse developmental output. Furthermore, these reviews discuss how developmental patterning relies on the convergence, divergence and integration of diverse signaling pathways. The order of the reviews in this issue follows these general themes. The first reviews discuss new results on the fundamental mechanisms underlying asymmetric cell division, developmental timing and cell signaling. The next set of reviews discuss how similar signaling pathways may elicit highly specific cellular responses, and how complex developmental patterns result from integration of multiple signaling pathways. The last set of reviews discuss recent advances in understanding underlie complex and elegant examples patterning in vertebrates.
mechanisms that of developmental
Asymmetric cell division The reviews by Jacobs and Shapiro (pp 386391) and by Lu, Jan and Jan (pp 392-399) discuss how a mother cell divides asymmetrically to give two distinct daughter cells. Mother cells can be intrinsically asymmetric, and have lineage determinants that are asymmetrically distributed prior to cell division. Lineage determinants specify distinct cell fates when they become segregated unequally different daughter cells following cell division, Work
the past year has led to the discovery of the ‘holy grail’ that regulates asymmetric cell division in yeast (AshlP) and in Caulobacter (CtrA). There has also been striking progress on how the PAR proteins in worms and numb and prosper0 in flies regulate asymmetric cell division. There now appear to be adaptor proteins that link the lineage determinants to protein machines, resulting in proper protein localization within the mother cell. Interestingly, each of the lineage determinants discussed in these reviews has a completely different protein sequence and yet there are similar mechanistic themes amongst these
Pattern formation and developmental
of the mother
The next set of reviews deal with the major conserved signaling pathways: the Hedgehog, Wnt, Notch, BMP/TGF-fi and Ras signaling pathways. As these signaling pathways can be found in virtually all animals, each of these reviews uses many species points about a single signaling pathway.
The excellent review by Gumbiner (pp 430435) focuses on the exciting discovery that the Wnt signal is transduced by a major protein complex, consisting of P-catenin, APC, Axin and GSK-3. It is particularly interesting that the \Vnt pathway controls cell polarity in C. elegans. The polarity of certain asymmetric cell divisions are controlled by a Wnt (encoded by /i/1-44) and by a Frizzled receptor (encoded by h-17) [l,Z]. Recent evidence shows that the VUUNgenes encode components of the Wnt signaling pathway, and regulate cell polarity of the EMS blastomere in embryogenesis. Weinmaster
a good overview
model of Notch receptor activation, both via the Su(H) transcription factor and independently of Su(H). Tivo elegant papers have recently provided direct evidence that the cytoplasmic tail of Notch is proteolytically enters the nucleus, and thereby regulates gene along with Su(H) [3,4].
The review by Cho and Blitz on TGF-B signaling (pp 443449) shows the richness of intracellular and extracellular mechanisms for regulating this signaling pathway, and points to the complexity of the interactions between
Johnson and Scott (pp 450-456) present an elegant review of the Hedgehog signaling pathway, in which they discuss a key breakthrough involving a costalZ/fused/cubitus interuptus protein complex that transduces the hedgehog signal downstream of the Patched and smoothened receptors. There has been recent excitement in the last year by the discovery that constitutive activation of the hedgehog signaling pathway (through inactivation of the Patched receptor), leads to basal cell carcinoma, a common form of skin tumor. Di Gregorio and Levine (pp 457463) offer an excellent overview of the importance of comparative approaches in dissecting the &-regulatory targets of developmental patterning signals. The parallels and differences that are emerging between ascidian and vertebrate development should offer important lessons on both the functioning and evolution of developmental mechanisms.
The observation that many diverse developmental outcomes are regulated by a few key signaling pathways
leads to the following question about signaling specificity. How can a commonly-used signaling pathway lead to distinct outcomes in different cells? The receptor tyrosine kinase/Ras/MAP kinase signaling pathway has diverse effects on a large number of tissues, such as neuronal differentiation and epithelial proliferation. Signaling specificity of the RTI
An exciting series of papers reviewed by Tsunoda, Sierralta and Zuker (pp 419-422), primarily studying activation of the photoreceptor in Drosophila, have shown that signal transduction proteins can be assembled into protein complexes called transducisomes. The scaffolding protein INAD simultaneously binds several key transducers in the phototransduction cascade. Once assembled into a protein complex, the transduction molecules may be able to efficiently relay the signal from the photoreceptor, increasing the sensitivity of the signaling pathway. Furthermore, the transducisome may play a role in signaling specificity by directing which transduction molecules interact with each other. A related issue of developmental specificity is discussed in the review by Mann and Affolter (pp 423429) on the mechanism of body patterning by Hox proteins. All Hox proteins encode transcription factors with very similar DNA-binding domains, and yet they can specify completely different parts of the body plan. In the past year, important discoveries have been made showing that Hox proteins can form complexes with PBC and Hth/Meis, which are two proteins that also contain homeodomains. Formation of these complexes may help regulate DNA binding specificity, and dictate when and where different Hox proteins
may be active.
Organizing pattern through signaling pathways
The last series of reviews in this issue of Curre?~ Opinion in Genetics B Dewlopment discuss developmental systems that are relatively more complex-such as axis formation in embryos, branching morphogenesis in the lung, and skeletal formation. The general theme in these reviews is that pattern formation in these systems results from the interaction of multiple signaling pathways, forming an integrated network capable of specifying complex and diverse patterns. The review by Schier and Talbot (pp 464-471) is a nice synthesis of the multiple cues involved in axis formation in the fish. The authors discuss the first success of positional cloning in this system, present mutants obtained in the screen for defective early axis formation, and describe
Editorial overview Kim and Fraser
in the zebrafish
and in Xetropzrs. The contribution from Newman-Smith and Rothman (pp 472-480) presents the integration of maternal and zygotic signals involved in patterning the as well as discussing the RNAi approach nematode, for the rapid production of gene knock-outs. Branching morphogenesis is a central aspect of lung development in mammals and tracheal development in DrosopMa. One
(pp 481-486) mechanisms morphogenesis
is that there are similarities in the underlying and genetic pathways regulating branching in these diverse systems. Another theme
is that morphogenesis is the result of multiple pathlvays acting as a regulatory network.
1). Finally, the review by Dunlap (pp 40WM6) points out the underlying mechanistic principles of circadian clocks, focusing primarily on recent work in Neurospora and Drosophila. The core circuit is a feedback loop, in which clock regulatory proteins control circadian processes and also inhibit their own synthesis or activity. The autoinhibitory feedback loop leads to cyclic expression of the clock regulatory protein, and the precise phase of the circadian rhythm is set by external stimuli such as the light/dark cycle.
References hlcGrew and PourquiC (pp 487-493) discuss the patterning of vertebrate somites. In addition to spatially coordinating the conserved Notch signaling pathway along the anterior/posterior axis, this review emphasizes the importance of temporal regulation of Notch signaling, and how somitic patterning may employ a molecular clock. The review by Komori and Kishimoto (pp 494-499) discusses bone formation by first discussing its origin from osteoclasts and chondrocytes, and then discussing
Herman MA, Horvitz HR: The Caenorhabditis elegans gene h-44 controls the polarity of asymmetric cell divisions. Development 1994, 120:1035-l 047.
Sawa H, Lobe1 L, Horvitz HR: The Caenorhabditis elegans gene /in-17. which is reauired for certain asvmmetric cell divisions. encodes a putative seven-transmembrane protein similar to the Drosophila Frizzled. Genes Dev 1996, IO:21 89-2197.
Schroeter EH, Kisslinger JA, Kopan R: Notch-l signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998, 393:382-386.
Struhl G, Adachi A: Nuclear access and action of notch in ho. Cell 1996, 93:649-660.