Development of the central and peripheral nervous systems in the lamprey

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1 Develop. Growth Differ. (2009) 51, doi: /j X x Blackwell Publishing Asia Review Development of the central and peripheral nervous systems in the lamprey Yasunori Murakami* and Aki Watanabe Department of Biology, Faculty of Science, Ehime University, 2-5, Bunkyo-cho, Matsuyama, , Japan Vertebrate brains are highly organized structures that show remarkable diversity throughout the animal groups. Among the vertebrates, the agnathan animals, which diverged from the gnathostomes early in the evolution of the vertebrates, occupy a key phylogenetic position in order to clarify the origin and evolution of the brain. We found that the lamprey brain has the basic molecular mechanisms necessary to form brain compartments. Conversely, the telencephalon and cerebellum display gnathostome-specific developmental mechanisms. We also propose that, in contrast to those of gnathostomes, the maxillary ramus of the trigeminal nerve and buccal ramus of the nerve on the anterior lateral line are not fused in the developing lamprey. Thus, the development of the central nervous system and the framework of the peripheral nerve around the oral region are thought to have improved in the course of the agnathan gnathostome transition. Key words: brain evolution, development, lamprey, lateral line system, trigeminal system. The vertebrate brain Vertebrate brains serve as the important center for various animal functions. As animal morphology shows remarkable diversity, vertebrate brains also evolve various structures that link tightly to their specific functions. The chondrichthyan fishes, sharks and rays, which are highly sensitive to chemicals in the water, possess a large olfactory bulb to process the sense of smell. On the other hand, birds and reptiles, which depend mainly on the visual system, have a highly organized optic tectum. Mammals have a six-layered neocortex in the telencephalon. Among vertebrates, the teleost hindbrain has various specialized structures. For example, in the Ostariophysians, the hindbrain region receives input from neurons that innervate thousands of taste buds on their extraoral and intraoral surfaces. These taste system-related hindbrain neurons create characteristic bulges called facial, glossopharyngeal, and vagus lobes (Johnston 1906). In particular, the *Author to whom all correspondence should be addressed. bothrops@sci.ehime-u.ac.jp Received 30 October 2008; revised 04 December 2008; accepted 12 December Journal compilation 2009 Japanese Society of Developmental Biologists internal structure of vagus lobes consists of a series of nine layers of neurons with a complex organization. In siluriformes fishes, the facial lobes receive input from the trigeminal ganglion and process somatosensory information. Interestingly, a kind of catfish, Ictalurus punctatus, has a barbel-derived somatotopic map in the facial lobe of its hindbrain (Herrick 1906; Marui et al. 1988; Kiyohara & Caprio 1996; Kiyohara et al. 1999). Moreover, in two families of snakes, the Boidae and the Viperidae, a pit organ detects infrared (IR) radiation (Hartline 1974). These animals have a specific nucleus in the hindbrain and distinct neuronal pathway called the lateral descending system to process IR sensation (reviewed by Molenaar 1992). The development of the vertebrate nervous system Despite their diversity, developing vertebrate brains share a common morphology. During early developmental stages, the vertebrate central nervous system shows transversely oriented bulges called neuromeres (von Baer 1828; Orr 1887; Bergquist & Källén 1953b; Vaage 1969; Fraser et al. 1990; Puelles & Rubenstein 1993). These neuromeres function to constitute fundamental morphological units (Bergquist & Källén 1953a,b). Importantly, neuromeres are present during the developmental period in all vertebrates, including agnathans (Bergquist

2 198 Y. Murakami and A. Watanabe Fig. 1. Expression of brain-related regulatory genes in the lamprey. The lamprey and gnathostome brain consist of a series of bulges called neuromeres and those in the hindbrain are called rhombomeres (r). The trigeminal (TG) and the facial nerve (VIIG) enter into r2 and r4, respectively. Lamprey Krox20 and EphC are restricted in r3 and r5 and Hox genes are expressed co-linearly in the hindbrain. Lamprey Pax2/ 5/8 and fgf8/17 are expressed in the mid-hindbrain boundary, and Otx is expressed in the midbrain and forebrain. Pax6 and Dlx1/6 genes are co-expressed in the anterior-dorsal diencephalon. Expression of Nkx2.1 is restricted in the ventral diencephalon, the hypothalamus. Emx is expressed in the dorsal part of the telencephalon. In the mouse, the expression patterns of regulatory genes are similar to the lamprey. However, in contrast to the lamprey, Pax6 has an expression domain in the dorsal hindbrain. Nkx2.1 and Sonic hedgehog (Shh) are expressed in the ventral telencephalon. ANR, anterior neural ridge; Di, diencephalon; Epi, epiphysis; HB, hindbrain; Hpt, hypothalamus; MB, midbrain; MHB, mid-hindbrain boundary; r1 6, rhombomeres; Tel, telencephalon; TG, trigeminal ganglion; VIIG, facial ganglion; ZLI, zona limitans intrathalamica. & Källén 1953a). Therefore, the basic structure of the vertebrate brain seems to have been established at an early evolutionary stage. The expression patterns of brain-marker genes that are involved in the early patterning of brain compartments closely correspond to morphological boundaries of neuromeres and the combination of expression patterns of those genes are highly conserved in gnathostomes (Puelles & Rubenstein 1993; Puelles et al. 2000; Nakamura 2001). In the developing lamprey brain, the expression patterns of regulatory genes are basically similar to those of gnathostomes (Fig. 1). Notably, vertebrate brain have some morphological centers such as the mid-hindbrain boundary (MHB) and the zona limitans intrathalamica (ZLI) (Joyner et al. 2000; Simeone 2000; Wurst & Bally-Cuif 2001; Echevarria et al. 2003). In the lamprey, molecular markers of the MHB and the ZLI could be observed; therefore, the basic developmental program for building the vertebrate central nervous system was already established in a very early phylogenic period (Ogasawara 2000; Murakami et al. 2001b, 2004; Osorio et al. 2005; Takio et al. 2007; Fig. 1). The putative early Cambrian agnathan Haikouichthys, from Chengjiang in China, has eyes and nasal sacs as well as what may be otic capsules, indicating that the vertebrate bauplan were advanced in the Early Cambrian period (Shu et al. 2003). The origin of brain compartments, therefore, might date back 540 million years. In addition to the brain compartments, developing vertebrate embryos have a series of specific neuronal tracts called the early axonal scaffold. These first tracts are highly conserved throughout vertebrates (Chitnis & Kuwada 1990; Easter et al. 1993; Figdor & Stern 1993; Anderson & Key 1999; Ishikawa et al. 2004). Because these early tracts appear

3 Development of the lamprey brain 199 to guide the later-developing neurons, they are important for the morphogenesis of subsequently developing complex neuronal circuits. In other words, these tracts are thought to provide the basic framework of the vertebrate brain. Importantly, these tracts extend along the boundaries of the expression domains of several transcription factors (Mastick et al. 1997). In the lamprey, the developing brain contains these early tracts and its morphology is comparable to that of the gnathostomes, suggesting that the mechanisms underlying the basic neuronal circuits were established in this common ancestor of vertebrates (Kuratani et al. 1998; Barreio- Iglesias et al. 2008). It is important to note that the developmental program for the brain shows a quite conservative aspect. In spite of the basic homology of the brain component, lamprey Nkx2.1 homologue (LjNkx2.1) and hha (hedgehog A), a putative homologue of gnathostome Sonic hedgehog (Shh) have no expression domain in the lamprey telencephalon (Murakami et al. 2005; Osorio et al. 2005; Fig. 1). It has been known that these genes play an important role for the morphogenesis of the gnathostome telencephalon (Sussel et al. 1999; Marín et al. 2000; Rallu et al. 2002; Echevarria et al. 2003). Thus, it is likely that lamprey does not have an important morphogenetic center in the anterior forebrain. In amniotes, fibroblast growth factor 8 (fgf8) is expressed in the anterior neural ridge (ANR), a morphological center for the telencephalon, and has been shown to be crucial for the specification of the anterior areas of forebrain and telencephalic polarity (Echevarria et al. 2003). Lamprey fgf8/17(ljfgf8/17), a homologue of gnathostome fgf8 has been cloned and the expression pattern studied (Shigetani et al. 2002; Uchida et al. 2003). However, Ljfgf8/17 is expressed in the olfactory placode that is close to the telencephalon, therefore, it is difficult to identify whether it is expressed in the telencephalon or not (Fig. 1). Further analysis is necessary to confirm the presence or absence of the ANR in the lamprey. Moreover, lamprey Pax6 is not expressed in the dorsal side of rhombomere 1(r1) that corresponds to the cerebellar primordium and the rhombic lip (Engelkamp et al. 1999; Murakami et al. 2001b). This is consistent with morphological observations that the lamprey cerebellum possesses only small corpus cerebelli in which gnathostome-like Purkinje and granule cells are lacking (Nieuwenhuys 1967; Nieuwenhuys & Nicholson 1998). The adult lamprey also lacks the inferior olive that derives through cell migration from the rhombic lip (Nieuwenhuys 1967). Thus, the gnathostome-like cerebellum and cerebellarrelated nuclei are thought to have emerged in the gnathostome lineage. Development of the vertebrate peripheral nervous system All vertebrates studied so far have a well-developed peripheral nervous system. Among them, branchial neurons including the trigeminal, facial, and vagus nerves innervate pharyngeal arch-derived structures. The octavolateralis system, including the lateral line, vestibular, and auditory systems, also innervate the craniofacial region. These peripheral nerves provide not only an important landmark for the comparative study of the craniofacial region, but also a basic framework for the peripheral neuronal network of the sensory system. A comparative analysis of the developing peripheral nervous system is thought to be important for understanding the evolution of the vertebrate sensory system. The two distinct peripheral nervous systems that innervate the oral apparatus are the trigeminal and lateral line systems. The trigeminal system in the lamprey In mammals, the trigeminal ganglion that innervates the first branchial arch-derived region is divided into three parts based on the receptive fields of each branch. The first branch, called the ophthalmic nerve, innervates the skin of the head, the non-visual parts of the eye, and the snout. The second branch, known as the maxillary nerve, innervates the upper jaw including the upper teeth, the roof of the mouth, and the upper lip. The third, or mandibular branch, innervates the lower jaw structures including the lower teeth, the floor of the mouth, and the lower lip (Butler & Hodos 1996). The trigeminal complex also contains a deep ophthalmic ramus, known as the profundal nerve. Ophthalmic and profundal nerves have their own ganglion that is separated, in many gnathostomes, from the ganglion of maxillary and mandibular nerve, and the profundal ganglion develops under a distinct molecular signal (Baker et al. 1999; O Neill et al. 2007). Afferents from the ophthalmic profundal and maxillomandibular ganglia enter specific parts of the hindbrain via a specialized structure called the nerve root. Importantly, in the developing gnathostome brain, the trigeminal nerve attaches specifically in r2 (Neal 1896; Tello 1923; Lumsden & Keynes 1989; Noden 1991; Gilland & Baker 1993). In the developing shark, Scyliorhinus, the ophthalmic and maxillomandibular trigeminal ganglion have been observed, and their peripheral branches innervate the head and jaw apparatus as they do in the other gnathostomes (Kuratani & Horigome 2000; O Neill et al. 2007; Fig. 2B,C). However, their trigeminal nerve root attaches to r3 due to the secondary shift (Kuratani & Horigome 2000; Fig. 3).

4 200 Y. Murakami and A. Watanabe are also divided into three sub-branches, apical, basilar and suborbital nerves (Koyama et al. 1987). The ophthalmic nerve has its own ganglion similar to that of the profundal ganglion in gnathostomes (Fig. 3). The maxillary and mandibular branches in the lamprey arise from the trigeminal ganglion, and innervate the upper lip and the velum, respectively (Johnston 1905; Kuratani et al. 1997; Fig. 2A). The trigeminal nerve enters the hindbrain via a nerve root attached in r2 (Kuratani et al. 1997; Murakami et al. 2004; Fig. 3). It is clear that the trigeminal system is established before the acquisition of the jaw. However, the homology of the lamprey maxillary nerve in relation to gnathostomes is still obscure. The maxillary ramus of the lamprey trigeminal nerve contains motor nerves by contrast to gnathostomes whose motor nerve is restricted in the mandibular nerve (Song & Boord 1993). Johnston (1905) mentioned that the lamprey mandibular nerve is partly incorporated into the maxillary nerve because it contains an efferent from the trigeminal motor nucleus. A separation of motor fiber-containing mandibular ramus from the maxillary nerve seems to be a gnathstome-specific feature. On the other hand, although the topographic projection patterns of trigeminal afferents in the lamprey are similar to those in gnathostomes, the somatotopy of the lamprey trigeminal ganglion appears to be inverted in relation to the gnathostomes (Koyama et al. 1990; Kuratani et al. 2004). Further analysis using molecular markers is necessary to identify the homology of lamprey trigeminal branches. Fig. 2. Morphology of the developing trigeminal and lateral line nerves. (A) Lateral view of the st. 27 lamprey (Lethenteron japonicum). (B) Ventrolateral view of the shark embryo (Scyliorhinus tirazame: stage VI: Kuratani & Horigome 2000). (C) Lateral view of the shark embryo. (D) Lateral view of the developing teleost, Pagrus major (120 h post fertilization). (E) Lateral view of the Xenopus embryo (stage 28). Large arrowheads indicate the close association of the ophthalmic trigeminal nerve (Oph) and the superficial ophthalmic ramus of the lateral line nerve (SO). Small arrowheads indicate the mandibular nerve (white arrowheads) and the ventral ramus of the anteroventral lateral line nerve (orange arrowheads), respectively. Arrows indicate the association of the trigeminal nerves (Mx/Md) and the lateral line nerves (B/AV). ALLG, anterior lateral line ganglion; AV, the ventral ramus of the anteroventral lateral line nerve; hyo, hyomandibular ramus of the lateral line nerve; Mx, maxillary nerve; Md, mandibular nerve; Opt, ophthalmic nerve; SO, superficial ophthalmic nerve; TG, trigeminal ganglion. In the lamprey, the trigeminal ganglion develops in a manner similar to that in the gnathostomes and the developing trigeminal system contains three branches named ophthalmic, maxillary, and mandibular rami (Kuratani et al. 1997; Fig. 2A). Lamprey maxillary nerves The lateral line system in the lamprey The aquatic anamniotes have a well-developed lateral line system (Wicht & Northcutt 1995; Butler & Hodos 1996). The lateral line system is simply divided into mechanosensory and electrosensory systems. These nerves innervate receptors called neuromast and ampullary organs that are located in a series of grooves or canals on the head and body. Among lateral line nerves, the electrosensory system has appeared independently in several vertebrate lineages including lamprey, Chondrichthyes, lungfish (Lepidosiren), Coelacanth (Latimeria), polypteriformes, Chondrostei (Polyodon), teleosts, and amphibians (Bullock et al. 1983). The lateral line nerves, including the anterodorsal, anteroventral, otic, middle, supratemporal, and posterior lateral line nerves, innervate the mechanoreceptors and electroreceptors (Northcutt 1997). These nerves are derived from the lateral line placodes and developing neurons have a nerve root attached to the dorsal side of r4 (Kuratani & Horigome 2000). In the shark embryo, the superficial ophthalmic and buccal rami appear from the anterior lateral line ganglion that is fused with the facial ganglion (Kuratani

5 Development of the lamprey brain 201 Fig. 3. Relationship between trigeminal and lateral line nerves. In the developing lamprey, the ophthalmic trigeminal nerve (Opt) is fused with the ophthalmic lateral line nerve (SO). However, the maxillary ramus (Mx) does not make contact with the buccal ramus of the anterior lateral line nerve (B), and so both of these nerves extend in independent pathways. In addition, the mandibular ramus of the trigeminal nerve (Md) overlaps only partially with the ventral ramus of the lateral line nerve (hyo). The shark maxillary nerve (Mx) and buccal lateral line nerve (B) make contact with each other to form a buccal and maxillary complex. The mandibular ramus of the trigeminal nerve (Md) also associates with the ventral ramus of the anteroventral lateral line nerve (AV). In the developing teleosts, the trigeminal and lateral line nerves fuse very tightly so that they cannot be identified as separate nerves. AV, the ventral ramus of the anteroventral lateral line nerve; hyo, hyomandibular ramus of the lateral line nerve; Mx, maxillary nerve; Md, mandibular nerve; Opt, ophthalmic nerve; PV, profundal ganglion; r, rhombomeres; SO, superficial ophthalmic nerve; TG, trigeminal ganglion. & Horigome 2000; Fig. 2C). The superficial ophthalmic ramus extends rostrally from the ganglion to innervate lateral line organs of the supraorbital line, and the buccal ramus extends ventrally from the ganglion to innervate lateral line organs of the infraorbital line (O Neill et al. 2007). The lateral line and facial nerves enter the hindbrain via a nerve root attached to r4 as they do in the other gnathostomes (Kuratani & Horigome 2000; Fig. 3). In the lamprey, the lateral line system consists of both mechanosensory and electrosensory systems, and possesses anterior and posterior lateral line nerves (Koyama et al. 1990). The anterior lateral line nerve that innervates the facial and oral regions has superficial ophthalmic, buccal, and recurrent branches (Ronan & Northcutt 1987; Koyama et al. 1990; Kuratani et al. 1997). These neurons appear in the developing lamprey from the anterior lateral line ganglion that is very close to the facial ganglion and attaches to r4 (Fig. 3). Relationship between trigeminal and lateral line nerves in vertebrates In gnathostomes, the ophthalmic or profundal trigeminal nerve is closely associated with the superficial ophthalmic nerves of anterodorsal lateral line nerve, and in many cases, the maxillary trigeminal ramus fuses with the buccal ramus of the anterodorsal lateral-line nerve to form a buccal and maxillary complex (Northcutt & Bemis 1993; Piotrowski & Northcutt 1996; Fig. 2D and 3). Furthermore, the mandibular ramus of the trigeminal nerve lies close to the ventral ramus of the anteroventral lateral-line nerve (Northcutt & Bemis 1993; Figs 2B,C and 3). This status has been observed in almost all aquatic gnathostomes including shark, chimeras (Cole 1896), Polypterus (Piotrowski & Northcutt 1996), coelacanth (Latimeria: Northcutt & Bemis 1993), and amphibians (Amblystoma: Johnston 1906). This link between trigeminal and lateral line nerves seems to be important functionally because it facilitates the integration of somatosensory and lateral line information. Indeed, afferents of somatosensory and lateral line systems in the teleost Sebastiscus marmoratus finally project to the dorsal telencephalon named area dorsalis telencephali pars medialis (Dm: Ito et al. 1986; Murakami et al. 1986). In developing gnathostome embryos, the shark maxillary and lateral line nerves extend to the same root, and make contact with each other in the distal-most part of the innervation area (Fig. 2B,C). The mandibular ramus of the trigeminal nerve also associates with the ventral ramus of the anteroventral lateral line nerve (Figs 2C and 3). In the teleost, Pagrus major, the maxillary and the buccal rami are closely associated with each other in course of the development so that they are difficult to identify as separate nerves (Figs 2D and 3). Because these nerves run through the same pathway during their axon guidance, they appear to be influenced by the same guidance molecules. In rodents, the developing maxillary ramus is attracted by bone morphogenetic protein 4 (BMP4) signals that derive from the oral ectoderm, and Smad4-dependent pathways in the

6 202 Y. Murakami and A. Watanabe Fig. 4. The presumptive evolutionary process of the vertebrate sensory systems. trigeminal neuron possibly regulate the spatial patterns of the trigeminal branches (Hodge et al. 2007). It is important to note that, in gnathostomes, the lateral-line nerve might respond to the BMP-based signaling pathway. In the developing lamprey, the ophthalmic trigeminal nerve is associated with the ophthalmic lateral line nerve and extends rostrally, as it does in gnathostomes (Fig. 2A). However, the maxillary ramus of the trigeminal nerve does not make contact with the buccal ramus of the anterior lateral line nerve, and so both of these nerves extend in independent pathways (Kuratani et al. 1997; Fig. 2A). In addition, the mandibular ramus of the trigeminal nerve overlaps only partially with the ventral ramus (hyomandubular nerve) of the lateral line nerve (Fig. 2A). The molecular mechanisms establishing the neuronal framework in the ophthalmic region seem to be conserved through vertebrates because both the trigeminal and lateral line nerves extend to the same root, whereas the axon guidance mechanisms in the first arch-derived region seem to be improved in the gnathostome lineage. This appears to be linked to the dramatic morphological changes in the oral apparatus that occurred in the agnathan gnathostome transition. However, it is important to note that in the developing lamprey, the upper and lower lips express BMP2/4a in a similar manner to the gnathostomes (Shigetani et al. 2002; McCauley & Bronner-Fraser 2004). Thus, at least the lamprey trigeminal neuron may respond to the BMP signal as it does in gnathostomes. Evolution of the sensory circuit All vertebrates have well-developed sensory systems, and the characteristic sensory circuits have evolved in each animal in relation to its lifestyle. Visual and somatosensory pathways that relay through collothalamic and lemnothalamic pathways are present in all amniotes (Butler & Hodos 1996). An ascending auditory pathway has been found in all amniotes. An olfactory epithelium and olfactory bulbs have been identified in all vertebrates including cyclostomes, suggesting that the basic unit of the main olfactory system appears in the common ancestor of vertebrates (Fig. 4). In contrast, vomeronasal receptors and an accessory olfactory bulb have been identified in amphibians, but not in teleosts. These brain units, therefore, are thought to have been acquired in the ancestor of tetrapods (Fig. 4). Among amniotes, the mammalian vomeronasal system is essential for interspecies communication using pheromonal cues. In squamate reptiles (lizards and snakes), the vomeronasal system is normally used for the sense of natural chemicals and this system is used, in snakes and monitors, to follow odorant trails on the substrate. Interestingly, the vomeronasal system is absent in sauropsids (crocodiles turtles and birds), suggesting that this system was lost after the divergence of squamates and sauropsids (Fig. 4). As noted above, the lateral line system appeared in the cyclostomes. Although hagfish appear to lack this

7 Development of the lamprey brain 203 system, the lateral line of hagfish has been observed transiently in their developmental process (Wicht & Northcutt 1995). The lateral line system is entirely lost in amniotes; therefore, the six lateral line nerves are absent in the common ancestor of amniotes. This may be related to the terrestrial shift of their lifecycles. In place of the loss of the lateral line system, a welldeveloped cochlea is found in mammals and diapsids. Therefore, the VIII nerve in amniotes is often called the vestibulocochlear nerve. The developmental mechanism underlying these sensory systems has not been well studied. However, some studies have shown that there are attractive and repulsive molecules involved in the process of axonal target recognition and axon guidance (Serafini et al. 1996; Tessier-Lavigne & Goodman 1996; Flanagan & Vanderhaeghen 1998). Interestingly, some genes that encode membrane-bound proteins are specifically expressed in individual sensory circuits such as the somatosensory, auditory, visual, and olfactory systems (Murakami et al. 2001a). Because lampreys have sensory systems including olfactory, visual, somatosensory, and lateral line systems, to better understand them it is important to study the origin of the developmental mechanisms underlying these sensory circuits. Future analyses in the lamprey using marker genes for these neuronal circuits are important to identify the evolution of sensory systems. Summary Cephalochordates (Amphioxus) and Urochordates (tunicates) have an anteroposterior specification along the neuraxis, and also part of the neuronal repertoire including motor, sensory, and inter neurons (Fritzsch & Northcutt 1993; Lacalli et al. 1994; Knight et al. 2000; Lacalli 2001; Jackman & Kimmel 2002). However, their brain is simply like a tube, and neither morphological segments nor a peripheral ganglion can be observed (Lacalli et al. 1994; Wada & Satoh 2001). The basic architecture of the vertebrate brain seems to have been acquired after the divergence of the chordates and vertebrates. Our lamprey study has shown that the brain systems present before the divergence of agnathans and gnathostomes are thought to have been made by the establishment of basic combinations of the expression domain of regulatory molecules. On the other hand, it is clear that there is a great morphological gap between agnathans and gnathostomes, because of the dramatic changes of the developmental mechanisms through the heterotopic shift of the developmental pattern of the oral region (Shigetani et al. 2002). The enormous changes in the development of the oral region may affect the mechanisms underlying the development of the nervous system, and possibly caused the dramatic morphological and functional changes in the vertebrate brain. Because the largest morphological changes are demonstrated in the divergence of agnathans and gnathostomes, the establishment of several brain regions such as the basal telencephalon and the modification of the axonguidance mechanism for peripheral nerves seem to be linked to this evolutionary event. A comparative analysis of the developmental mechanisms between agnathans and gnathostomes may provide interesting findings in this field of evolutionary neuromorphology. Acknowledgments We thank Dr Shigeru Kuratani for valuable discussion. We also thank Dr Shigeki Hirano for an offer of lamprey embryos, Dr Hisato Iwata for teleost embryos, Dr Hiromi Takata for Xenopus laevis embryos, and Dr Koji Tamura for shark embryos. 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