Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-10-20
2001-08-07
Spector, Lorraine (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023510, C536S023100, C530S350000, C530S300000, C435S069100
Reexamination Certificate
active
06271363
ABSTRACT:
FUNDING
Work described herein was supported by funding from the National Institutes of Health. The United States Government has certain rights in the invention.
BACKGROUND OF THE INVENTION
Pattern formation is the activity by which embryonic cells form ordered spatial arrangements of differentiated tissues. The physical complexity of higher organisms arises during embryogenesis through the interplay of cell-intrinsic lineage and cell-extrinsic signaling. Inductive interactions are essential to embryonic patterning in vertebrate development from the earliest establishment of the body plan, to the patterning of the organ systems, to the generation of diverse cell types during tissue differentiation (Davidson, E., (1990)
Development
108: 365-389; Gurdon, J. B., (1992)
Cell
68: 185-199; Jessell, T. M. et al., (1992)
Cell
68: 257-270). The effects of developmental cell interactions are varied. Typically, responding cells are diverted from one route of cell differentiation to another by inducing cells that differ from both the uninduced and induced states of the responding cells (inductions). Sometimes cells induce their neighbors to differentiate like themselves (homoiogenetic induction); in other cases a cell inhibits its neighbors from differentiating like itself. Cell interactions in early development may be sequential, such that an initial induction between two cell types leads to a progressive amplification of diversity. Moreover, inductive interactions occur not only in embryos, but in adult cells as well, and can act to establish and maintain morphogenetic patterns as well as induce differentiation (J. B. Gurdon (1992)
Cell
68:185-199).
The origin of the nervous system in all vertebrates can be traced to the end of gastrulation. At this time, the ectoderm in the dorsal side of the embryo changes its fate from epidermal to neural. The newly formed neuroectoderm thickens to form a flattened structure called the neural plate which is characterized, in some vertebrates, by a central groove (neural groove) and thickened lateral edges (neural folds). At its early stages of differentiation, the neural plate already exhibits signs of regional differentiation along its anterior posterior (A-P) and mediolateral axis (M-L). The neural folds eventually fuse at the dorsal midline to form the neural tube which will differentiate into brain at its anterior end and spinal cord at its posterior end. Closure of the neural tube creates dorsal/ventral differences by virtue of previous mediolateral differentiation. Thus, at the end of neurulation, the neural tube has a clear anterior-posterior (A-P), dorsal ventral (D-V) and mediolateral (M-L) polarities (see, for example,
Principles in Neural Science
(3
rd
), eds. Kandel, Schwartz and Jessell, Elsevier Science Publishing Company: NY, 1991; and
Developmental Biology
(3
rd
), ed. S. F. Gilbert, Sinauer Associates: Sunderland, Mass., 1991). Inductive interactions that define the fate of cells within the neural tube establish the initial pattern of the embryonic vertebrate nervous system. In the spinal cord, the identify of cell types is controlled, in part, by signals from two midline cell groups, the notochord and floor plate, that induce neural plate cells to differentiate into floor plate, motor neurons, and other ventral neuronal types (van Straaten et al. (1988)
Anat. Embryol.
177:317-324; Placzek et al. (1993)
Development
117:205-218; Yamada et al. (1991)
Cell
64:035-647; and Hatta et al. (1991) Nature 350:339-341). In addition, signals from the floor plate are responsible for the orientation and direction of commissural neuron outgrowth (Placzek, M. et al., (1990)
Development
110: 19-30). Besides patterning the neural tube, the notochord and floorplate are also responsible for producing signals which control the patterning of the somites by inhibiting differentiation of dorsal somite derivatives in the ventral regions (Brand-Saberi, B. et al., (1993)
Anat. Embryol.
188: 239-245; Porquie, O. et al., (1993)
Proc. Natl. Acad Sci. USA
90: 5242-5246).
Another important signaling center exists in the posterior mesenchyme of developing limb buds, called the Zone of Polarizing Activity, or “ZPA”. When tissue from the posterior region of the limb bud is grafted to the anterior border of a second limb bud, the resultant limb will develop with additional digits in a mirror-image sequence along the anteroposterior axis (Saunders and Gasseling, (1968)
Epithelial
-
Mesenchymal Interaction,
pp. 78-97). This finding has led to the model that the ZPA is responsible for normal anteroposterior patterning in the limb. The ZPA has been hypothesized to function by releasing a signal, termed a “morphogen”, which forms a gradient across the early embryonic bud. According to this model, the fate of cells at different distances from the ZPA is determined by the local concentration of the morphogen, with specific thresholds of the morphogen inducing successive structures (Wolpert, (1969)
Theor. Biol.
25:1-47). This is supported by the finding that the extent of digit duplication is proportional to the number of implanted ZPA cells (Tickle, (1981)
Nature
254:199-202).
A candidate for the putative ZPA morphogen was identified by the discovery that a source of retinoic acid can result in the same type of mirror-image digit duplications when placed in the anterior of a limb bud (Tickle et al., (1982)
Nature
296:564-565; Summerbell, (1983)
J. Embryol
78:269-289). The response to exogenous retinoic acid is concentration dependent as the morphogen model demands (Tickle et al., (1985)
Dev. Biol.
109:82-95). Moreover, a differential distribution of retinoic acid exists across the limb bud, with a higher concentration in the ZPA region (Thaller and Eichele, (1987)
Nature
327:625-628).
Recent evidence, however, has indicated that retinoic acid is unlikely to be the endogenous factor responsible for ZPA activity (reviewed in Brockes, (1991)
Nature
350:15; Tabin, (1991)
Cell
66:199-217). It is now believed that rather than directly mimicking an endogenous signal, retinoic acid implants act by inducing an ectopic ZPA. The anterior limb tissue just distal to a retinoic acid implant and directly under the ectoderm has been demonstrated to acquire ZPA activity by serially transplanting that tissue to another limb bud (Summerbell and Harvey, (1983)
Limb Development and Regeneration
pp. 109-118; Wanek et al., (1991)
Nature
350:81-83). Conversely, the tissue next to a ZPA graft does not gain ZPA activity (Smith, (1979)
J. Embryol
52:105-113). Exogenous retinoic acid would thus appear to act upstream of the ZPA in limb patterning.
The immediate downstream targets of ZPA action are not known. However, one important set of genes which are ectopically activated during ZPA-induced pattern duplications are the 5′ genes of the Hoxd cluster. These genes are normally expressed in a nested pattern emanating from the posterior margin of the limb bud (Dolle et al., (1989)
Nature
342:767-772; Izpisua-Belmonte et al., (1991)
Nature
350:585-589). This nested pattern of Hox gene expression has been directly demonstrated to determine the identity of the structures produced along the anteroposterior axis of the limb (Morgan et al., (1993)
Nature
358:236-239). As this would predict, ZPA grafts which produce mirror-image duplication of structures at an anatomical level first lead to the ectopic activation of the Hoxd genes in a mirror-image duplication at the molecular level. (Nohno et al., (1991)
Cell
64:1197-1205; Izpisua-Belmonte et al., (1991)
Nature
350:585-589). The molecular signals which regulate the expression of these important genes are currently not understood.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a novel family of genes, and gene products, expressed in vertebrate organisms, which genes referred to hereinafter as the “hedgehog” gene family, the products of which are referred to as hedgehog proteins. The products of the hedgehog gene have apparent broad involvement in the formation and maintena
Ingham Philip W.
McMahon Andrew P.
Tabin Clifford J.
Foley Hoag & Eliot LLP
Kaufman Claire M.
President & Fellows of Harvard College
Spector Lorraine
Varma Anita
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