There is a great range of limb forms amongst the members of the animal kingdom; from the brachiating primates to the flying bats, through various media including the air, ground and water
 |
| The Different Forms of Limb diversity. From top left going clockwise; Pongo borneo, a braciator; Equus equus, a runner; Felis catus; a cetacean, limb used as a flipper; Ursa arctos claw (Brown Bear); Condylura cristata using it’s limbs for digging; a Ciconiidae using limbs to fly (after WordPress, 2010) |
These endless forms of limbs have evolved to cope with many different environments and other evolutionary stresses, including predator prey relations outlined in The Red Queen principle. (Ridley, 1995) These stresses, due to their varied nature have produced remarkable forms of limbs and other morphological adaptions. (Darwin, 1859)
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| Proposed phylogeny of limb developments (Ahlberg & Clack, 2006) |
In 1937, Theodosius Dobzhansky published Genetics and the Origin of Species, a book in which he outlined the new biological philosophy of Neo-Darwinism (New World Encyclopedia, 2011). Neo-Darwinism is the marrying of two important biological theories, that of Genetics, as outlined by Mendel and Evolution as outlined by Darwin. This fundamental paradigm shift in the scientists of today, allows for the study of morphometry and the genetic basis for a alteration thereof.
“… a study of the effects of genes during development is as essential for an understanding of evolution as are the study of mutation and that of selection.”
(Huxley, 1942)
The modern synthesis of palaeontology evolutionary and developmental biology has shown that there are genes that determine many morphological adaptions; however, these genes are homologous and conserved over many divergent lineages. This is predicted from evolutionary theory due to the existence of a common ancestor for all extant biota.
“While restricted to form, nevertheless this theory has a synthetic character. It considers the nature of mutations and their effects on fitness, applies across taxonomic and time scales, and offers a causal explanation that links changes in genes to alterations in development and the evolution of form. It thus has important implications for and many fruitful areas of overlap with other disciplines such as population genetics and paleontology.”
(Carroll, 2008)
The limb is divided into three distinct sections, namely stylopod, consisting of the humerus; zeugopod, made up of the radius and ulna; and autopod, incorporating the hand, wrist and fingers. All tetrapod limbs consist of these three basic elements (Niswander, 2003)
The limb is formed by the initial bud outgrowth of the Apical Ectodermal Rdge (AER). This outgrowth is initiated by Fibroblast Growth Factor 10 (FGF10) (Mariani & Martin, 2003). The spatial and temporal expression of FGF10 is controlled by Tbx5 and Tbx4, in conjunction with Pitx1 in the forelimb and hindlimb respectively. (Logan, 2003)
The proximal distal patterning of the limb is contolled by collinear expression of the HoxD complex, with the scapula, humerus, radius and ulna, carpels and metacarpels, and phalanges or tarsals being coded for by HoxD9 to HoxD13 respectively (Davis, Witte, Hsieh-Li, Potter, & Capecchi, 1995). The expression of these gene products in conjuction with Meis1 and Meis2 , which is expressed in the proximal region of the limb bud, suppressing gene products for the distal patterning of limbs (Mercader, et al., 1999), allows for the full proximodistal patterning of the limb to arise.
In Serpentes, the majority of vertebrae are transformed into thoracic vertebrae, thorough the expansion of the expression domains to allow for HoxB5 and HoxC6 to overlap, leading to no forelimbs being formed. However, serpentes do have vestigial hindlimbs (Cohn & Tickle, 1999)
The Anterior Posterior axis of the limb is also controlled by genetic means. The Zone of Polarising Activity (ZPA) occurs at the posterior of the limb and is present in the limb from the initial bud outgrowth. The ZPA produces a protein called Sonic Hedgehog (Shh) which is, itself, a transcription factor (Bastida & Ros, 2008). The Shh then forms a concentration gradient across the anterior posterior axis of the hand and allowing for number and identity of digits to be determined. The temporal activity of SHH is also of grave importance, as ectopic expression may result in a greater number of digits forming (Yang, et al., 1997). As Shh signalling decreases with time, the differential digits are formed. Digit two has only paracrine signalling of SHH, whilst digit three to five have autocrine signalling of Shh over a temporal expression pattern.
The Shh signalling cascade allows for the two protein complex, Smoothened (Smo) and Patched (Ptc) to break apart, causing for Patched to bind with Shh which allows for Smo to activate Cubitus interruptus (Ci) by releasing it from the microtubules, allowing it to act as a positive transcription factor in the nucleus. When Shh is absent, Ci acts as a repressor in the nucleus, stopping the transcription of genes.
The human condition, Greig polysyndactyly, is caused by the mutation of the Gli genes, which are the mammalian orthologues of Ci. The Gli genes have differential function, as does Ci, depending on whether Shh are present or absent. If Shh is present, Gli acts as an activator, whilst when Shh is absent Gli acts as a repressor (Litingtung, Dahn, Li, Fallon, & Chiang, 2002)
The collinear expression of the Hox complex is reversed in certain circumstances (Monteiro & Ferrier, 2006). This has been shown to occur during anterior posterior patterning of the hand and allows for the development of a thumb which is independent of Shh paracrine signalling (Montavo, Le Garrec, Kerszberg, & Duboule, 2009)
The number of limbs is a fundamental morphological difference between animals, with number of limbs ranging from four to more than 10. The number of limbs appears to be conserved between classes, which allows for the analysis of gene mutations in deep geological time.
The insects are a taxon in which all members have six legs. When a comparison of insect and other invertebrates was performed, it appeared that Insect Ultra-bithorax (Ubx), an important gene for limb spatial placement, had a poly-alanine repeat in the functional protein that the remaining taxa did not. Ubx inhibits the activity of distal-less, and therefore suppresses limb growth in the abdominal region. However, Brachiopod crustaceans Ubx is expressed throughout the body but does not suppress limb development. (Ronshaugen, McGinnis, & McGinnis, 2002)
The change in expression pattern has been a gradual shifting towards the posterior of the boundary of Ubx and AbdA. This would have resulted from small mutations in the cis-coding regulatory element (CRE) of the gene. This, in various environments may have been favourable (Dawkins, 1982), and thus natural selection selected or the more posterior Ubx and AbdA boundary (Averof & Akan, 1995).
The transformation of crustacean limbs into maxillipeds is caused by the loss of Ubx in the corresponding segments, this implies that through the course of crustacean evolution, the spatial expression pattern of Ubx has shifted, allowing for the range of varied appendages that is visible in the phylum. (Pavlopoulosa, Kontarakis, Liubicich, Serano, Patel, & Averof, 2009)
Tbx4 and Tbx5 have been shown to be deep homologues, with their function being conserved over deep time. Amphioxus Tbx4/5 is sufficient to initiate limb outgrowth in mice and produce functional limbs, however, a domain swap show that they do not play a role in limb identity. (Minguillon, Gibson-Brown, & Logan, 2009)
The amphioxus uniform Tbx4/5 does not allow for forelimb and hindlimb specificity to differ. However, with the duplication event in the lineage of vertebrates, Tbx4 spatial expression has been allowed to differ from that of Tbx5. This would allow for a more divergent forelimb to hindlimb profile. This is achieved by mutations of the cis-regulatory regions of TBX4 and TBX5, which have changed the spatial expression pattern of Tbx4 and Tbx5 to allow for more specialised limbs. (Minguillon, Gibson-Brown, & Logan, 2009) This mutation to allow for separate hindlimb and forelimb identities would have been favoured by natural selection due to the less specialised, two pairs of different limbs that now could be developed. This has allowed for a more broad range of ecologies in which the organisms can exist, which increases their fitness and is thus favoured by natural selection.
Actinopterygian fish have been shown to develop limbs in the same fashion as tetrapods, including the reverse collinear expression of the HoxD complex in the fin. This implies the possibility of the presence of digits in fish. The presence of digits has been long considered a trademark of tetrapods by classical taxonomy (Davis, Dahn, & Shubin, 2007). The presence thus, of paired limbs in fish can therefore be attributed to the change of expression of Tbx4 and Tbx5, which implies common ancestry amongst the entire vertebrate lineage.
The presence of carpel and tarsal homologues has been shown in fish, implying the underlying deep homology between fish and tetrapods. Hoxd expression is driven by cis-enhancer elements, thought to be limited to the tetrapod lineage. However, the Hoxd CsB enhancer has been shown to be present in fish revealing the deep homology between of the autopod segment. (Schneider, Aneas, Gehrke, Dahn, Nobrega, & Shubin, 2011).
This deep homology is one of the underlying principles of the Theory of Evolution, with shared appendages. The above results imply that new morphological adaptions do not arise de novo, but are exapted from the pre-existing genetic circuits of the ancestral metazoan (Shubin, Tabin, & Carroll, 2009)
“These advances in understanding the assembly of the tetrapod limb push the issue of limb origins further back in time. […] Both arthropod appendages and tetrapod limbs develop as outgrowths of the body wall that are patterned along three axes — the proximodistal, anteroposterior and dorso-ventral axes — often using homologous genes to establish the ordinate axes. If the extraordinary similarities between arthropod and vertebrate appendages reflect the homology of patterning mechanisms, those mechanisms should be present in basal deuterostomes.”
(Shubin, Tabin, & Carroll, 2009)
Within the class of mammals, development of the limb is conserved; however, cis-regulatory elements change the dosage effect of the genes. This has been observed when a CRE element of a bat was placed into a mouse, creating a significantly longer limb phenotype (Cretekos, et al., 2008).
This change in the CRE of the mouse Prx1 allowed for an increased dosage of Prx1, which resulted in the elongated limb phenotype. It can therefore be construed that the Bat CRE has either a differential temporal expression pattern of Prx1 or that the rate of transcription from the enhancer element is higher.
Gene duplication has played an important role in evolution (Ohno, 1970), however, for the spatial and temporal expression patterns of the gene to change, a mutation of the CRE is necessary. It has been shown that the CRE of Prx1 has been successively duplicated in Mus musculus. (Cretekos, et al., 2008)
All the above genes are not solely active in the limb, but may are expressed in many organs development, including, but not limited to the brain and heart. Significantly, FGF10 and SHH have been shown to play a role in beak development in chickens, where a knockout mutation leads to the development to a structure analogous to an alligator’s snout (Abzhanov, Protas, Grant, Grant, & Tabin, 2004). This further emphasises the deep homology between these developmental genes.
SHH has also been shown to play a role in Pharyngeal Arch development (Garga, Chihiro Yamagishia, Hua, Kathiriyaa, Yamagishia, & Srivastavaa, 2001), neuroderm development (Pabst, Herbrand, Takuma, & Arnold, 1999) and brain (Roessler, et al., 1996)
Development can be likened to a troop of dancers (after Dawkins, 2009), with each individual gene following cues from each other in order to structure the entire body. The ballet of development has only started to be understood.
Many works can be authored on the wealth of knowledge, that is and will be conducted, on the development of limbs, let alone the development of the other countless specialised regions of the body. Nevertheless, the ideology that the diversity of limbs can be accounted for by small mutations in the CRE and coding region of the gene has been seen to hold throughout the entire biota extant today. This research has provided a firm foundation for the theory of evolution. (Smith, 2003)
Limbs have evolved through countless pressures imposed on them by selective agents, including, but not limited to predator-prey interactions and other ecological pressures. The number of animals extant account for approximately 1% of all biota that have existed on the planet. The differential patterns of limbs that have existed on this planet from the dawn of life are inconceivable.
“Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”
The modern synthesis of palaeontology evolutionary and developmental biology has shown that there are genes that determine many morphological adaptions; however, these genes are homologous and conserved over many divergent lineages. This is predicted from evolutionary theory due to the existence of a common ancestor for all extant biota.
“While restricted to form, nevertheless this theory has a synthetic character. It considers the nature of mutations and their effects on fitness, applies across taxonomic and time scales, and offers a causal explanation that links changes in genes to alterations in development and the evolution of form. It thus has important implications for and many fruitful areas of overlap with other disciplines such as population genetics and paleontology.”
(Carroll, 2008)
The limb is divided into three distinct sections, namely stylopod, consisting of the humerus; zeugopod, made up of the radius and ulna; and autopod, incorporating the hand, wrist and fingers. All tetrapod limbs consist of these three basic elements (Niswander, 2003)
The limb is formed by the initial bud outgrowth of the Apical Ectodermal Rdge (AER). This outgrowth is initiated by Fibroblast Growth Factor 10 (FGF10) (Mariani & Martin, 2003). The spatial and temporal expression of FGF10 is controlled by Tbx5 and Tbx4, in conjunction with Pitx1 in the forelimb and hindlimb respectively. (Logan, 2003)
The proximal distal patterning of the limb is contolled by collinear expression of the HoxD complex, with the scapula, humerus, radius and ulna, carpels and metacarpels, and phalanges or tarsals being coded for by HoxD9 to HoxD13 respectively (Davis, Witte, Hsieh-Li, Potter, & Capecchi, 1995). The expression of these gene products in conjuction with Meis1 and Meis2 , which is expressed in the proximal region of the limb bud, suppressing gene products for the distal patterning of limbs (Mercader, et al., 1999), allows for the full proximodistal patterning of the limb to arise.
In Serpentes, the majority of vertebrae are transformed into thoracic vertebrae, thorough the expansion of the expression domains to allow for HoxB5 and HoxC6 to overlap, leading to no forelimbs being formed. However, serpentes do have vestigial hindlimbs (Cohn & Tickle, 1999)
The Anterior Posterior axis of the limb is also controlled by genetic means. The Zone of Polarising Activity (ZPA) occurs at the posterior of the limb and is present in the limb from the initial bud outgrowth. The ZPA produces a protein called Sonic Hedgehog (Shh) which is, itself, a transcription factor (Bastida & Ros, 2008). The Shh then forms a concentration gradient across the anterior posterior axis of the hand and allowing for number and identity of digits to be determined. The temporal activity of SHH is also of grave importance, as ectopic expression may result in a greater number of digits forming (Yang, et al., 1997). As Shh signalling decreases with time, the differential digits are formed. Digit two has only paracrine signalling of SHH, whilst digit three to five have autocrine signalling of Shh over a temporal expression pattern.
The Shh signalling cascade allows for the two protein complex, Smoothened (Smo) and Patched (Ptc) to break apart, causing for Patched to bind with Shh which allows for Smo to activate Cubitus interruptus (Ci) by releasing it from the microtubules, allowing it to act as a positive transcription factor in the nucleus. When Shh is absent, Ci acts as a repressor in the nucleus, stopping the transcription of genes.
The human condition, Greig polysyndactyly, is caused by the mutation of the Gli genes, which are the mammalian orthologues of Ci. The Gli genes have differential function, as does Ci, depending on whether Shh are present or absent. If Shh is present, Gli acts as an activator, whilst when Shh is absent Gli acts as a repressor (Litingtung, Dahn, Li, Fallon, & Chiang, 2002)
The collinear expression of the Hox complex is reversed in certain circumstances (Monteiro & Ferrier, 2006). This has been shown to occur during anterior posterior patterning of the hand and allows for the development of a thumb which is independent of Shh paracrine signalling (Montavo, Le Garrec, Kerszberg, & Duboule, 2009)
The number of limbs is a fundamental morphological difference between animals, with number of limbs ranging from four to more than 10. The number of limbs appears to be conserved between classes, which allows for the analysis of gene mutations in deep geological time.
The insects are a taxon in which all members have six legs. When a comparison of insect and other invertebrates was performed, it appeared that Insect Ultra-bithorax (Ubx), an important gene for limb spatial placement, had a poly-alanine repeat in the functional protein that the remaining taxa did not. Ubx inhibits the activity of distal-less, and therefore suppresses limb growth in the abdominal region. However, Brachiopod crustaceans Ubx is expressed throughout the body but does not suppress limb development. (Ronshaugen, McGinnis, & McGinnis, 2002)
The change in expression pattern has been a gradual shifting towards the posterior of the boundary of Ubx and AbdA. This would have resulted from small mutations in the cis-coding regulatory element (CRE) of the gene. This, in various environments may have been favourable (Dawkins, 1982), and thus natural selection selected or the more posterior Ubx and AbdA boundary (Averof & Akan, 1995).
 |
| Limbs of Jasus lalandii showing the Ultra Bithorax (Ubx) concentration gradient along the posterior anterior axis of the organism. (Photo: J. Davies. 2011) |
Tbx4 and Tbx5 have been shown to be deep homologues, with their function being conserved over deep time. Amphioxus Tbx4/5 is sufficient to initiate limb outgrowth in mice and produce functional limbs, however, a domain swap show that they do not play a role in limb identity. (Minguillon, Gibson-Brown, & Logan, 2009)
The amphioxus uniform Tbx4/5 does not allow for forelimb and hindlimb specificity to differ. However, with the duplication event in the lineage of vertebrates, Tbx4 spatial expression has been allowed to differ from that of Tbx5. This would allow for a more divergent forelimb to hindlimb profile. This is achieved by mutations of the cis-regulatory regions of TBX4 and TBX5, which have changed the spatial expression pattern of Tbx4 and Tbx5 to allow for more specialised limbs. (Minguillon, Gibson-Brown, & Logan, 2009) This mutation to allow for separate hindlimb and forelimb identities would have been favoured by natural selection due to the less specialised, two pairs of different limbs that now could be developed. This has allowed for a more broad range of ecologies in which the organisms can exist, which increases their fitness and is thus favoured by natural selection.
Actinopterygian fish have been shown to develop limbs in the same fashion as tetrapods, including the reverse collinear expression of the HoxD complex in the fin. This implies the possibility of the presence of digits in fish. The presence of digits has been long considered a trademark of tetrapods by classical taxonomy (Davis, Dahn, & Shubin, 2007). The presence thus, of paired limbs in fish can therefore be attributed to the change of expression of Tbx4 and Tbx5, which implies common ancestry amongst the entire vertebrate lineage.
The presence of carpel and tarsal homologues has been shown in fish, implying the underlying deep homology between fish and tetrapods. Hoxd expression is driven by cis-enhancer elements, thought to be limited to the tetrapod lineage. However, the Hoxd CsB enhancer has been shown to be present in fish revealing the deep homology between of the autopod segment. (Schneider, Aneas, Gehrke, Dahn, Nobrega, & Shubin, 2011).
This deep homology is one of the underlying principles of the Theory of Evolution, with shared appendages. The above results imply that new morphological adaptions do not arise de novo, but are exapted from the pre-existing genetic circuits of the ancestral metazoan (Shubin, Tabin, & Carroll, 2009)
“These advances in understanding the assembly of the tetrapod limb push the issue of limb origins further back in time. […] Both arthropod appendages and tetrapod limbs develop as outgrowths of the body wall that are patterned along three axes — the proximodistal, anteroposterior and dorso-ventral axes — often using homologous genes to establish the ordinate axes. If the extraordinary similarities between arthropod and vertebrate appendages reflect the homology of patterning mechanisms, those mechanisms should be present in basal deuterostomes.”
(Shubin, Tabin, & Carroll, 2009)
Within the class of mammals, development of the limb is conserved; however, cis-regulatory elements change the dosage effect of the genes. This has been observed when a CRE element of a bat was placed into a mouse, creating a significantly longer limb phenotype (Cretekos, et al., 2008).
This change in the CRE of the mouse Prx1 allowed for an increased dosage of Prx1, which resulted in the elongated limb phenotype. It can therefore be construed that the Bat CRE has either a differential temporal expression pattern of Prx1 or that the rate of transcription from the enhancer element is higher.
Gene duplication has played an important role in evolution (Ohno, 1970), however, for the spatial and temporal expression patterns of the gene to change, a mutation of the CRE is necessary. It has been shown that the CRE of Prx1 has been successively duplicated in Mus musculus. (Cretekos, et al., 2008)
All the above genes are not solely active in the limb, but may are expressed in many organs development, including, but not limited to the brain and heart. Significantly, FGF10 and SHH have been shown to play a role in beak development in chickens, where a knockout mutation leads to the development to a structure analogous to an alligator’s snout (Abzhanov, Protas, Grant, Grant, & Tabin, 2004). This further emphasises the deep homology between these developmental genes.
SHH has also been shown to play a role in Pharyngeal Arch development (Garga, Chihiro Yamagishia, Hua, Kathiriyaa, Yamagishia, & Srivastavaa, 2001), neuroderm development (Pabst, Herbrand, Takuma, & Arnold, 1999) and brain (Roessler, et al., 1996)
Development can be likened to a troop of dancers (after Dawkins, 2009), with each individual gene following cues from each other in order to structure the entire body. The ballet of development has only started to be understood.
Many works can be authored on the wealth of knowledge, that is and will be conducted, on the development of limbs, let alone the development of the other countless specialised regions of the body. Nevertheless, the ideology that the diversity of limbs can be accounted for by small mutations in the CRE and coding region of the gene has been seen to hold throughout the entire biota extant today. This research has provided a firm foundation for the theory of evolution. (Smith, 2003)
Limbs have evolved through countless pressures imposed on them by selective agents, including, but not limited to predator-prey interactions and other ecological pressures. The number of animals extant account for approximately 1% of all biota that have existed on the planet. The differential patterns of limbs that have existed on this planet from the dawn of life are inconceivable.
“Thus, from the war of nature, from famine and death, the most exalted object which we are capable of conceiving, namely, the production of the higher animals, directly follows. There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”
(Darwin, 1859)
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Averof, M., & Akan, M. (1995). Hox genes and the diversification of insect and crustacean body plans. Nature , 420-423.
Bastida, M., & Ros, M. (2008). How do we get a perfect complement of digits? Current Opinion in Genetics & Development , 374–380.
Carroll, S. (2008). Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution. Cell , 25-36.
Cohn, M., & Tickle, C. (1999). Developmental Basis of Limblessness and Axial Patterning in Snakes. Nature , 474-479.
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Bibliography
Abzhanov, A., Protas, M., Grant, B., Grant, P., & Tabin, C. (2004). Bmp4 and Morphological Variation of Beaks in Darwin's Finches. Science , 1462-1465.
Ahlberg, E., & Clack, J. (2006). Palaeontology: A firm step from water to land. Nature , 747-749.
Averof, M., & Akan, M. (1995). Hox genes and the diversification of insect and crustacean body plans. Nature , 420-423.
Bastida, M., & Ros, M. (2008). How do we get a perfect complement of digits? Current Opinion in Genetics & Development , 374–380.
Carroll, S. (2008). Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution. Cell , 25-36.
Cohn, M., & Tickle, C. (1999). Developmental Basis of Limblessness and Axial Patterning in Snakes. Nature , 474-479.
Cretekos, C., Wang, Y., Green, E., Martin, J., Rasweiler, J., Behringer, R., et al. (2008). Regulatory divergence modifies limb length between mammals. Genes and Development , 141–151.
Darwin, C. (1859). On the Origin of Species (1 ed.). (D. Quammen, Ed.) London: Sterling.
Davis, A., Witte, P., Hsieh-Li, H., Potter, S., & Capecchi, M. (1995). Absence of radius and ulna in mice lacking hoxa-11 and hoxd-11. Nature , 791-795.
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