Question 1

In humans the HOXD homeotic gene cluster plays a critical role in limb development. In one large family, 16 of 36 members expressed one of two dominantly inherited malformations of the feet known as rocker bottom foot (CVT) or claw foot (CMT). One individual had one foot with CVT and the other with CMT. Genomic analysis identified a missense mutation in the HOXD10 gene, resulting in a single amino acid substitution in the homeodomain of the encoded transcription factor. This region is crucial for making contact and binding to the target genes controlled by this protein. All family members with the foot malformations were heterozygotes; all unaffected members were homozygous for the normal allele.
Given that affected heterozygotes carry one normal allele of the HOXD10 gene, how might a dominant mutation in a gene encoding a transcription factor lead to a developmental malformation?

Accepted Answer

A dominant mutation in a heterozygote has one mutant allele and one normal allele. The mutant phenotype is expressed, in spite of the normal functioning allele. This is because most dominant mutations are gain-of-function mutations in which the mutant gene is overexpressed or produces a gene product that is more active than the gene product produced by the normal allele. Therefore, the mutant gene product "beats" the normal gene product and the mutant phenotype is observed. 
In the case of the mutated HOXD10 gene, the binding domain of the transcription factor is mutated. Most likely the mutation increases the binding affinity of the transcription factor. This would cause the mutated transcription factor to bind deoxyribonucleic acid (DNA) or other proteins more readily than the normal transcription factor, resulting in the mutant phenotype being expressed.

Question 2

In this chapter, we have focused on large-scale as well as the inter- and intracellular events that take place during embryo-genesis and the formation of adult structures. In particular, we discussed how the adult body plan is laid down by a cascade of gene expression, and the role of cell-cell communication in development. Based on your knowledge of these topics, answer several fundamental questions:
(a) How do we know how many genes control development in an organism like Drosophila ?
(b) What experimental evidence demonstrates that molecular gradients in the egg control development?
(c) How did we discover that selector genes specify which adult structures will be formed by body segments?
(d) How did we learn about the levels of gene regulation involved in vulval development in C. elegans ?
(e) How do we know that eye formation in all animals is controlled by a binary switch gene?

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Question 3

In humans the HOXD homeotic gene cluster plays a critical role in limb development. In one large family, 16 of 36 members expressed one of two dominantly inherited malformations of the feet known as rocker bottom foot (CVT) or claw foot (CMT). One individual had one foot with CVT and the other with CMT. Genomic analysis identified a missense mutation in the HOXD10 gene, resulting in a single amino acid substitution in the homeodomain of the encoded transcription factor. This region is crucial for making contact and binding to the target genes controlled by this protein. All family members with the foot malformations were heterozygotes; all unaffected members were homozygous for the normal allele.
How can two clinically different disorders result from the same mutation?

Accepted Answer

The HOXD10 gene is a homeotic gene that plays a large role in limb formation during embryogenesis. It encodes a transcription factor which binds deoxyribonucleic acid (DNA) or other proteins causing activation or inactivation. Development involves the complex interaction of multiple genes and the transcription factor encoded by the HOXD10 gene probably serves multiple purposes during limb development. Therefore, the mutated transcription factor would be capable of producing multiple mutant phenotypes. 
This is particularly apparent in the individual with congenital vertical talus (CVT) in one foot and Charcot-Marie-Tooth (CMT) disease in the other foot. Both feet are affected by a mutated transcription factor during limb development, but each foot was affected in a slightly different way.

Question 4

Review the Chapter Concepts list. These all center around concepts related to stages of development. Write a short essay based on these concepts that outlines the role of differential transcription, gene control of cell fate, and the role of signaling systems in development.
▪Gene expression during development is based on the differential transcription of selected genes.
▪Animals use a small number of shared signaling systems and regulatory networks to construct a wide range of adult body forms from the zygote. These shared properties make it possible to use animal models to study human development.
▪Differentiation is controlled by cascades of gene expression that are a consequence of events that specify and determine the developmental fate of cells.
▪Plants independently evolved developmental regulatory mechanisms that parallel those of animals.
▪In many organisms, binary switch genes program the developmental fate of embryonic cells.

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Question 5

In humans the HOXD homeotic gene cluster plays a critical role in limb development. In one large family, 16 of 36 members expressed one of two dominantly inherited malformations of the feet known as rocker bottom foot (CVT) or claw foot (CMT). One individual had one foot with CVT and the other with CMT. Genomic analysis identified a missense mutation in the HOXD10 gene, resulting in a single amino acid substitution in the homeodomain of the encoded transcription factor. This region is crucial for making contact and binding to the target genes controlled by this protein. All family members with the foot malformations were heterozygotes; all unaffected members were homozygous for the normal allele.
What might we learn about the control of developmental processes from an understanding of how this mutation works?

Accepted Answer

This mutation suggests that small changes in the proteins encoded by the HOXD gene cluster control nearly all aspects of limb development. A single missense mutation that alters the binding region of the protein indicates the protein binds to various genes to control limb development. Congenital vertical talus (CVT) and Charcot-Marie-Tooth disease (CMT) in the same individual also suggests stochastic control of limb development. HOX mutations also indicate spatial and temporal order of expression of these genes during development as well as a colinear expression pattern of these genes in different parts of the body.

Question 6

Carefully distinguish between the terms differentiation and determination. Which phenomenon occurs initially during development?

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Question 7

Nuclei from almost any source may be injected into Xenopus oocytes. Studies have shown that these nuclei remain active in transcription and translation. How can such an experimental system be useful in developmental genetic studies?

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Question 8

Distinguish between the syncytial blastoderm stage and the cellular blastoderm stage in Drosophila embryogenesis.

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Question 9

What are maternal-effect genes?
(b) When are gene products from these genes made, and where are they located?
(c) What aspects of development do maternal-effect genes control?
(d) What is the phenotype of maternal-effect mutations?

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(b) When are gene...

Question 10

What are zygotic genes, and when are their gene products made?
(b) What is the phenotype associated with zygotic gene mutations?
(c) Does the maternal genotype contain zygotic genes?

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Question 11

List the main classes of zygotic genes. What is the function of each class of these genes?

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Question 12

Experiments have shown that any nuclei placed in the polar cytoplasm at the posterior pole of the Drosophila egg will differentiate into germ cells. If polar cytoplasm is transplanted into the anterior end of the egg just after fertilization, what will happen to nuclei that migrate into this cytoplasm at the anterior pole?

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Question 13

How can you determine whether a particular gene is being transcribed in different cell types?

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Question 14

You observe that a particular gene is being transcribed during development. How can you tell whether the expression of this gene is under transcriptional or translational control?

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Question 15

The homeotic mutation Antennapedia causes mutant Drosophila to have legs in place of antennae and is a dominant gain-of-function mutation. What are the properties of such mutations? How does the Antennapedia gene change antennae into legs?

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Question 16

The Drosophila homeotic mutation spineless aristapedia ( ss a ) results in the formation of a miniature tarsal structure (normally part of the leg) on the end of the antenna. What insight is provided by ( ss a ) concerning the role of genes during determination?

Accepted Answer

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Question 17

Embryogenesis and oncogenesis (generation of cancer) share a number of features including cell proliferation, apoptosis, cell migration and invasion, formation of new blood vessels, and differential gene activity. Embryonic cells are relatively undifferentiated, and cancer cells appear to be undifferentiated or dedifferentiated. Homeotic gene expression directs early development, and mutant expression leads to loss of the differentiated state or an alternative cell identity. M. T. Lewis (2000. Breast Can. Res. 2: 158-169) suggested that breast cancer may be caused by the altered expression of homeotic genes. When he examined 11 such genes in cancers, 8 were underexpressed while 3 were over-expressed compared with controls. Given what you know about homeotic genes, could they be involved in oncogenesis?

Accepted Answer

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Question 18

Early development depends on the temporal and spatial interplay between maternally supplied material and mRNA and the onset of zygotic gene expression. Maternally encoded mRNAs must be produced, positioned, and degraded (Surdej and Jacobs-Lorena, 1998. Mol. Cell Biol. 18: 2892-2900). For example, transcription of the bicoid gene that determines anterior-posterior polarity in Drosophila is maternal. The mRNA is synthesized in the ovary by nurse cells and then transported to the oocyte, where it localizes to the anterior ends of oocytes. After egg deposition, bicoid mRNA is translated and unstable bicoid protein forms a decreasing concentration gradient from the anterior end of the embryo. At the start of gastrulation, bicoid mRNA has been degraded. Consider two models to explain the degradation of bicoid mRNA: (1) degradation may result from signals within the mRNA (intrinsic model), or (2) degradation may result from the mRNA's position within the egg (extrinsic model). Experimentally, how could one distinguish between these two models?

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Question 19

Formation of germ cells in Drosophila and many other embryos is dependent on their position in the embryo and their exposure to localized cytoplasmic determinants. Nuclei exposed to cytoplasm in the posterior end of Drosophila eggs (the pole plasm) form cells that develop into germ cells under the direction of maternally derived components. R. Amikura et al. (2001. Proc. Nat. Acad. Sci. ( USA ) 98: 9133-9138) consistently found mitochondria-type ribosomes outside mitochondria in the germ plasma of Drosophila embryos and postulated that they are intimately related to germ-cell specification. If you were studying this phenomenon, what would you want to know about the activity of these ribosomes?

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Question 20

One of the most interesting aspects of early development is the remodeling ofthe cell cycle from rapid cell divisions, apparently lacking G1 and G2 phases, to slower cell cycles with measurable G1 and G2 phases and checkpoints. During this remodeling, maternal mRNAs that specify cyclins are deadenylated, and zygotic genes are activated to produce cyclins. Audic et al. (2001. Mol. and Cell. Biol. 21: 1662-1671) suggest that dead-enylation requires transcription of zygotic genes. Present a diagram that captures the significant features of these findings.

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Quiz 18: Developmental Genetics