Papers by Michael J. Depew
Developmental biology, 2001
The Alx gene family is implicated in craniofacial development and comprises two to four homeobox ... more The Alx gene family is implicated in craniofacial development and comprises two to four homeobox genes in each vertebrate genome analyzed. Using phylogenetics and comparative genomics, we show that the common ancestor of jawed vertebrates had three Alx genes descendent from the two-round genome duplications (Alx1, Alx3, Alx4), compared with a single amphioxus gene. Later in evolution one of the paralogues, Alx3, was lost independently from at least three different vertebrate lineages, whereas Alx1 and Alx4 were consistently retained. Comparison of spatial gene expression patterns reveals that the three mouse genes have equivalent craniofacial expression to the two chick and frog genes, suggesting that redundancy compensated for gene loss. We suggest that multiple independent loss of one Alx gene was predisposed by extensive and persistent overlap in gene expression between Alx paralogues. Even so, it is unclear whether it was coincidence or evolutionary bias that resulted in the same Alx gene being lost on each occasion, rather than different members of the gene family.
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Journal of Combinatorial Chemistry, 2001
The synthesis and use of an alkylsilyl-tethered large (500-600 µm) polystyrene resin (1) are disc... more The synthesis and use of an alkylsilyl-tethered large (500-600 µm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.
Methods Mol Biol, 2008
Among the symposia held at the seminal meeting of the European Society for Evolutionary Developme... more Among the symposia held at the seminal meeting of the European Society for Evolutionary Developmental Biology was one centered on the development and evolution of the vertebrate head, an exquisitely complex anatomical system. The articles presented at this meeting have been gathered in a special issue of the Journal of Experimental Zoology, and are here reviewed by the organizers of the symposia. These articles cover a breadth of subjects, including interactions between cells derived from the different germ layers, such as those underlying neural crest cell migration and fate and cranial muscle specification, as well as placode development and the origin, development, and evolution of important evolutionary innovations such as jaws and the trabecula cranii. In this introduction, we provide a short historical overview of themes of research into the fundamental organization, structure, and development of the vertebrate head, including the search for head segmentation and the relevance of the New Head Hypothesis, and subsequently present the topics discussed in each of the articles. This overview of the past and the present of head evo-devo is then followed by a glimpse at its possible future and a brief examination of the utility of the notions of heterochrony, heterotopy, and heterofacience in describing evolutionarily important changes in developmental events.
Journal of Experimental Zoology Part B-molecular and Developmental Evolution, 2008
Historically, examinations of gnathostome skulls have indicated that for essentially the entirety... more Historically, examinations of gnathostome skulls have indicated that for essentially the entirety of their existence, jaws have been characterized by a high degree of fidelity to an initial basic structural design that will then go on to manifest an amazing array of end-point phenotypes. These two traits-bauplan fidelity and elaboration of design-are inter-connected and striking, and beg a number of questions, including: Are all jaws made in the same manner and if not how not? To begin to tackle such questions, we herein operationally define jaws as two appositional, hinged cranial units for which polarity and potential modularity are characteristics, and then address what is necessary for them to form, including delineating both the sources of cells and tissues that will formally yield the jaws as well as what informs their ontogeny (e.g., sources of positional information and factors directing the interpretation of developmental cues). Following on this, we briefly describe a predictive, testable model of jaw development (the ''Hinge and Caps'' model) and present evidence that the Satb21cell population in the developing jaw primordia of mice defines a developmentally and evolutionarily significant jaw module such as would be predicted by the model.
Proceedings of The National Academy of Sciences, 2005
Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and... more Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest-specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1 -/mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1 -/background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3-q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations.
Developmental Dynamics, 2006
Classic neontology (comparative embryology and anatomy), through the application of the concept o... more Classic neontology (comparative embryology and anatomy), through the application of the concept of homology, has demonstrated that the development of the gnathostome (jawed vertebrate) skull is characterized both by a fidelity to the gnathostome bauplan and the exquisite elaboration of final structural design. Just as homology is an old concept amended for modern purposes, so are many of the questions regarding the development of the skull. With due deference to Geoffroy-St. Hilaire, Cuvier, Owen, Lankester et al., we are still asking: How are bauplan fidelity and elaboration of design maintained, coordinated, and modified to generate the amazing diversity seen in cranial morphologies? What establishes and maintains pattern in the skull? Are there universal developmental mechanisms underlying gnathostome autapomorphic structural traits? Can we detect and identify the etiologies of heterotopic (change in the topology of a developmental event), heterochronic (change in the timing of a developmental event), and heterofacient (change in the active capacetence, or the elaboration of capacity, of a developmental event) changes in craniofacial development within and between taxa? To address whether jaws are all made in a like manner (and if not, then how not), one needs a starting point for the sake of comparison. To this end, we present here a "hinge and caps" model that places the articulation, and subsequently the polarity and modularity, of the upper and lower jaws in the context of cranial neural crest competence to respond to positionally located epithelial signals. This model expands on an evolving model of polarity within the mandibular arch and seeks to explain a developmental patterning system that apparently keeps gnathostome jaws in functional registration yet tractable to potential changes in functional demands over time. It relies upon a system for the establishment of positional information where pattern and placement of the "hinge" is driven by factors common to the junction of the maxillary and mandibular branches of the first arch and of the "caps" by the signals emanating from the distal-most first arch midline and the lamboidal junction (where the maxillary branch meets the frontonasal processes). In this particular model, the functional registration of jaws is achieved by the integration of "hinge" and "caps" signaling, with the "caps" sharing at some critical level a developmental history that potentiates their own coordination. We examine the evidential foundation for this model in mice, examine the robustness with which it can be applied to other taxa, and examine potential proximate sources of the signaling centers. Lastly, as developmental biologists have long held that the anterior-most mesendoderm (anterior archenteron roof or prechordal plate) is in some way integral to the normal formation of the head, including the cranial skeletal midlines, we review evidence that the seminal patterning influences on the early anterior ectoderm extend well beyond the neural plate and are just as important to establishing pattern within the cephalic ectoderm, in particular for the "caps" that will yield medial signaling centers known to coordinate jaw development.
Journal of Clinical Investigation, 2007
Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and... more Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest-specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1 -/mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1 -/background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3-q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations.
American Journal of Human Genetics, 2006
The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorpho... more The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in ∼25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous—along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.
Developmental Biology, 2011
Classic neontology (comparative embryology and anatomy), through the application of the concept o... more Classic neontology (comparative embryology and anatomy), through the application of the concept of homology, has demonstrated that the development of the gnathostome (jawed vertebrate) skull is characterized both by a fidelity to the gnathostome bauplan and the exquisite elaboration of final structural design. Just as homology is an old concept amended for modern purposes, so are many of the questions regarding the development of the skull. With due deference to Geoffroy-St. Hilaire, Cuvier, Owen, Lankester et al., we are still asking: How are bauplan fidelity and elaboration of design maintained, coordinated, and modified to generate the amazing diversity seen in cranial morphologies? What establishes and maintains pattern in the skull? Are there universal developmental mechanisms underlying gnathostome autapomorphic structural traits? Can we detect and identify the etiologies of heterotopic (change in the topology of a developmental event), heterochronic (change in the timing of a developmental event), and heterofacient (change in the active capacetence, or the elaboration of capacity, of a developmental event) changes in craniofacial development within and between taxa? To address whether jaws are all made in a like manner (and if not, then how not), one needs a starting point for the sake of comparison. To this end, we present here a "hinge and caps" model that places the articulation, and subsequently the polarity and modularity, of the upper and lower jaws in the context of cranial neural crest competence to respond to positionally located epithelial signals. This model expands on an evolving model of polarity within the mandibular arch and seeks to explain a developmental patterning system that apparently keeps gnathostome jaws in functional registration yet tractable to potential changes in functional demands over time. It relies upon a system for the establishment of positional information where pattern and placement of the "hinge" is driven by factors common to the junction of the maxillary and mandibular branches of the first arch and of the "caps" by the signals emanating from the distal-most first arch midline and the lamboidal junction (where the maxillary branch meets the frontonasal processes). In this particular model, the functional registration of jaws is achieved by the integration of "hinge" and "caps" signaling, with the "caps" sharing at some critical level a developmental history that potentiates their own coordination. We examine the evidential foundation for this model in mice, examine the robustness with which it can be applied to other taxa, and examine potential proximate sources of the signaling centers. Lastly, as developmental biologists have long held that the anterior-most mesendoderm (anterior archenteron roof or prechordal plate) is in some way integral to the normal formation of the head, including the cranial skeletal midlines, we review evidence that the seminal patterning influences on the early anterior ectoderm extend well beyond the neural plate and are just as important to establishing pattern within the cephalic ectoderm, in particular for the "caps" that will yield medial signaling centers known to coordinate jaw development.
The Journal of …, 2003
The user has requested enhancement of the downloaded file. All in-text references underlined in b... more The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately.
Journal of …, 2005
Induction, neurogenesis, and synaptogenesis of the olfactory bulb are thought to require interact... more Induction, neurogenesis, and synaptogenesis of the olfactory bulb are thought to require interactions with the olfactory epithelium. The Dlx family of homeobox genes is expressed in both the olfactory bulb and olfactory epithelium. In particular, Dlx5 is expressed in the olfactory placode, olfactory epithelium, and local circuit neurons of the olfactory bulb. Here we analyzed mice lacking DLX5 function. The Dlx5 Ϫ/Ϫ mutation reduces the size of the olfactory epithelium. Although some olfactory neurons are formed, they fail to generate olfactory axons that innervate the olfactory bulb. Despite the lack of innervation, the olfactory bulb forms, and neurogenesis of projection and local circuit neurons proceeds. However, the mutation has a cell-autonomous effect on the ability of neural progenitors to produce olfactory bulb local circuit neurons, with granule cells more severely affected than periglomerular cells. In addition, the mutation has a noncell-autonomous effect on the morphogenesis of mitral cells.
…, 2001
The user has requested enhancement of the downloaded file. All in-text references underlined in b... more The user has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12. 5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. J. Neurosci. 13, 3155-3172. Chen, X., Li, X., Wang, W. and Lufkin, T. (1996) Dlx5 and Dlx6: an evolutionary conserved pair of murine homeobox genes expressed in the embryonic skeleton. Ann. New York Acad. Sci. 785, 38-47. (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125, 813-824. Corsin, J. (1971) Influence des placodes olfactives et des ebauches optiques sur la morphagenese du squelette cranien chez Pleurodeles waltii michah. Annales d'Embryologie et de morphogenese 1, 41-48. Couly, G. F. and Le Douarin, N. M. (1985) Mapping of the early neural primordium in quail-chick chimeras. I. Developmental relationships between placodes, facial ectoderm, and prosencephalon. Dev. Biol. 110, 422-439. Couly, G. F. and Le Douarin, N. M. (1987) Mapping of the early neural primordium in quail-chick chimeras. II. The prosencephalic neural plate and neural folds: implications for the genesis of cephalic human congenital abnormalities. Dev. Biol. 120, 198-214. Couly, G. F., Coltey, P. M. and Le Douarin, N. M. (1993) The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 117, 409-429. Characterization of the split hand/split foot malformation locus SHFM1 at 7q21. 3-q22. 1 and analysis of a candidate gene for its expression during limb development. Human Molecular Genetics 5, 571-579. (1998) Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nature Genetics 19, 125-133. De Beer, G. (1985) The Development of the Vertebrate Skull. Chicago: Univeristy of Chicago Press. Dollé, P., Price, M. and Duboule, D. (1992) Expression of the murine Dlx-1 homeobox gene during facial, ocular and limb development. Differentiation 49, 93-99. Eagleson, G., Ferreiro, B. and Harris, W. A. (1995) Fate of the anterior neural ridge and the morphogenesis of the Xenopus forebrain. J. Neurobiol. 28, 146-158. Eales, N. B. (1950) The skull of the foetal narwhal, Monodon monoceros L. Phil. Trans. Roy. Soc. London, B 235, 1-33. Ellies, D. L., Langille, R. M., Martin, C. C., Akimenko, M. A. and Ekker, M. (1997) Specific craniofacial cartilage dysmorphogenesis coincides with a loss of dlx gene expression in retinoic acid-treated zebrafish embryos. Mech. Dev. 61, 23-36. Ferrari, D., Sumoy, L., Gannon, J., Sun, H., Brown, A. M., Upholt, W. B. and Kosher, R. A. (1995) The expression pattern of the Distal-less homeobox-containing gene Dlx-5 in the developing chick limb bud suggests its involvement in apical ectodermal ridge activity, pattern formation, and cartilage differentiation. Mech. Dev. 52, 257-264. Expression of the mouse goosecoid gene during mid-embryogenesis may mark mesenchymal cell lineages in the developing head, limbs and body wall. Development 117,
…, 1999
Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12... more Spatially restricted expression of Dlx-1, Dlx-2 (Tes-1), Gbx-2, and Wnt-3 in the embryonic day 12. 5 mouse forebrain defines potential transverse and longitudinal segmental boundaries. J. Neurosci. 13, 3155-3172. Chen, X., Li, X., Wang, W. and Lufkin, T. (1996) Dlx5 and Dlx6: an evolutionary conserved pair of murine homeobox genes expressed in the embryonic skeleton. Ann. New York Acad. Sci. 785, 38-47. (1998) Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125, 813-824. Corsin, J. (1971) Influence des placodes olfactives et des ebauches optiques sur la morphagenese du squelette cranien chez Pleurodeles waltii michah. Annales d'Embryologie et de morphogenese 1, 41-48.
Scientometrics, 1999
Members of the LEF-1/TCF family of transcription factors have been implicated in the transduction... more Members of the LEF-1/TCF family of transcription factors have been implicated in the transduction of Wnt signals. However, targeted gene inactivations of Lef1, Tcf1, or Tcf4 in the mouse do not produce phenotypes that mimic any known Wnt mutation. Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a-deficient mice. In addition, Lef1 −/− Tcf1 −/− embryos have defects in the formation of the placenta and in the development of limb buds, which fail both to express Fgf8 and to form an apical ectodermal ridge. Together, these data provide evidence for a redundant role of LEF-1 and TCF-1 in Wnt signaling during mouse development.
Genes & …, 1999
Members of the LEF-1/TCF family of transcription factors have been implicated in the transduction... more Members of the LEF-1/TCF family of transcription factors have been implicated in the transduction of Wnt signals. However, targeted gene inactivations of Lef1, Tcf1, or Tcf4 in the mouse do not produce phenotypes that mimic any known Wnt mutation. Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a-deficient mice. In addition, Lef1 −/− Tcf1 −/− embryos have defects in the formation of the placenta and in the development of limb buds, which fail both to express Fgf8 and to form an apical ectodermal ridge. Together, these data provide evidence for a redundant role of LEF-1 and TCF-1 in Wnt signaling during mouse development.
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Papers by Michael J. Depew