digit 4 progenitors digit 5 progenitors Cells that make digit 4 and 5 and part

Digit 4 progenitors digit 5 progenitors cells that

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digit 4 progenitors digit 5 progenitors -Cells that make digit 4 and 5 (and part of digit 3) are direct descendants of Shh secreting cells. -Digit 5 cells spend more time exposed to Shh (autocrine) than cells in digit 4 -Digit 3 is specified by both time and Shh concentration (paracrine) -Digit 2 is specified by Shh concentration (paracrine) - Digit 1 is Shh-independent Shh effects are mediated by a gradient of BMP
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Shh (ZPA) dual role in A/P limb patterning 1. Long range Controls digit number: define the regions in the bud that are competent to form digits. 2. Short range Establish and maintains a BMP2 morphogen gradient that specifies digit identity. Adding BMP inhibitors (Noggin) to limbs treated with Shh: - extra digits still form but they are all the same type
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Regulation of digit identity by BMP in the interdigital space Noggin beads Removal of interdigital region 2 transforms digit 2 into digit 1 Removal of interdigital region 3 transforms digit 3 into digit 2 Placing beads soaked with noggin (BMP inhibitor) into the interdigital spaces causes the same effect BMP from Interdigital tissue specifies the identity of the digit anterior to it
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Signaling in forelimb development Positive feedback loop between AER and ZPA Ectoderm AER ZPA AER
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Dorso-Ventral limb axis Determined by the ectodermal tissue that surrounds the limb bud ( non-AER ectoderm ). Not by mesoderm. If ectoderm is rotated 180 o the dorsal-ventral polarity of the digits is reversed. Signaling molecules are expressed asymmetrically in the limb ectoderm: Wnt7a (dorsal) induces activation of Lmx1 (homeodomain) Engrailed (ventral) Lack of Wnt7a or LMx1 “ ventralizes ” limbs and digits (no nails, no knee caps). The boundary where dorsal and ventral ectoderm meet is essential for AER placement: dorsalized limbs do not form AER.
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Summary of signaling interactions in limb axes specification A. AER induction Ffg10 from mesenchyme (lateral plate mesoderm) activates Wnt3 in ectoderm. Wnt3 activates Fgf8 that in turns activates Fgf10 (positive feedback loop). BMP from ventral ectoderm activates Engrailed (En1) which represses Wnt7 . B. AER maintenance As limb grows: Shh from ZPA induces A-P polarity ( BMP gradient) Shh induces gremlin ( Grem1 ) an inhibitor of BMP which allows continued Fgf8 synthesis by the AER.
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Homework Mutations (loss of function) of Gli3 in both mice and humans causes polydactyly. Why?
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