The colonisation of land by tetrapods led to a series of independent solutions to the problem of adapting sensory systems from water to air. In particular, the auditory apparatus was modified several times through a mixture of alteration of ancestral structures and de novo innovations (Chagnaud et al., 2017; Fritzsch and Elliott, 2017; Fritzsch and Straka, 2014; Grothe and Pecka, 2014; Manley, 2000; Manley, 2017). These changes also required the evolution of associated neural processing networks in the hindbrain. Each extant neural circuit is therefore an elaboration of the remarkably conserved brainstem groundplan (Nieuwenhuys, 2011) and has been resourced from a repertoire of neural lineages that depicts an ancestral rhombomeric arrangement (Philippidou and Dasen, 2013; Wullimann et al., 2011).

The interplay between ancestral and de novo responses to changing environmental context is readily apparent when comparing the auditory and vestibular systems, which have interrelated developmental and evolutionary histories (Duncan and Fritzsch, 2012; Fritzsch and Straka, 2014; Manley et al., 2004). Both systems process mechanical stimuli and share an ancestral receptor cell type (the hair cells), which sit in specialised sensory epithelia located in the inner ear and develop from the same ectodermal thickening, the otic placode (Fritzsch and Elliott, 2017; Fritzsch and Straka, 2014; Whitfield, 2015). Vestibular sensory input has remained mostly unchanged and, correspondingly, vestibular peripheral organs, hindbrain vestibular nuclei and their projection patterns are highly conserved across vertebrates (Straka and Baker, 2013; Straka et al., 2014). All vertebrates possess a conserved set of vestibular sensory epithelia that project, via the eighth nerve, to a conserved set of hindbrain vestibular structures: superior, lateral (or Deiters), medial and descending (inferior or spinal) vestibular nuclei (Figure 1A).

Figure 1

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In contrast, the transition from an aquatic to a land environment brought about a marked transformation of the auditory scene and led to various specialisations for the detection of airborne sound (Carr and Christensen-Dalsgaard, 2016; Carr and Soares, 2002; Clack, 2015; Fritzsch and Straka, 2014; Grothe et al., 2004; Grothe and Pecka, 2014; Manley, 2000; Manley, 2017). Paleontological, morphological, functional and behavioural evidence suggests that a number of auditory peripheral and central innovations emerged separately in the different clades of land vertebrates (Grothe and Pecka, 2014; Manley, 2000; Manley, 2017; Manley et al., 2004). Most striking amongst them is the independent emergence during the Triassic period, more than 100 million years after the separation of the tetrapod lineages, of at least five variants of a tympanic middle ear, which operates as an impedance matching device for the efficient detection of airborne sounds (Anthwal et al., 2013; Carr and Christensen-Dalsgaard, 2016; Clack, 2015; Kitazawa et al., 2015; Manley, 2000; Tucker, 2017). This was accompanied by the independent elongation of the auditory sensory epithelia, a parallel diversification of hair cell types and concomitant elaborations of hair cell based sound amplification mechanisms, ultimately leading to fine tuning of sound detection and expansions of the hearing range to higher frequencies in several amniote clades (Dallos, 2008; Hudspeth, 2008; Köppl, 2011; Manley, 2000; Manley, 2017).

Alongside the independent emergence of middle and inner ear innovations, amniotes have developed neural mechanisms for processing sound stimulus of increasing frequency with increasing accuracy. As a result, the complement of brainstem auditory nuclei, the central targets of the auditory branch of the eighth nerve, varies greatly between clades and no true homologies could be established between them thus far (Carr and Christensen-Dalsgaard, 2016; Grothe et al., 2004; Nothwang, 2016). Mammals (the first clade to split from the ancestral amniote branch) possess two first order auditory nuclei, the ventral and dorsal cochlear nuclei. These project to second order hindbrain nuclei: lateral and medial superior olive and lateral and medial nucleus of the trapezoid body, as well as to other brainstem and higher order targets (Carr and Soares, 2002; Grothe et al., 2004) (Figure 1B). In diapsids (reptiles and birds), two first order nuclei receive auditory nerve afferents: the nucleus angularis and nucleus magnocellularis. These project as well to second order hindbrain nuclei (superior olivary nucleus and nucleus laminaris) and higher order structures (Carr and Soares, 2002; Grothe et al., 2004) (Figure 1C).

Notwithstanding the presence of such divergent arrays of hindbrain auditory structures, both mammals and archosaurs (birds and crocodilians) have developed mechanisms for sound source localisation based on hindbrain neural processing circuits. Functional analogies and convergent evolution have been proposed for some sub-circuits (Carr and Christensen-Dalsgaard, 2016; Carr and Soares, 2002; Grothe et al., 2010). An example is the interaural time difference (ITD) circuit that compares the difference in time of arrival of sound to each ear to determine the location of the sound source in the horizontal plane. In both mammals and archosaurs the overall organisation of the circuit is similar, with bilaterally projecting first order neurons that converge in coincidence detection neurons that are, in turn, modulated by inhibitory input (Figure 1D,E). However, a number of circuit features reveal that the functional analogy is only superficial and indicate that the ITD circuits are an example of convergent evolution (Carr and Christensen-Dalsgaard, 2016; Carr and Soares, 2002; Grothe et al., 2004; Grothe and Pecka, 2014; Grothe et al., 2010). Although coincidence detection neurons are present in both groups, only the avian connectivity resembles a Jeffres model circuit (Jeffress, 1948) (Figure 1E), with axonal delay lines that contact coincidence detection neurons arranged as a place code (Ashida and Carr, 2011; Grothe et al., 2010). Such a wiring pattern is not present in mammals (Grothe et al., 2010; Karino et al., 2011) (Figure 1D), and the ITD coding strategies differ between the two clades (Grothe and Pecka, 2014; Grothe et al., 2010). Moreover, inhibitory modulation plays different roles in avian and mammalian ITD circuits (Grothe, 2003; Grothe and Pecka, 2014).

The notable disparity between the highly conserved vestibular hindbrain and the independently elaborated auditory hindbrain provides a framework on which to interrogate the contribution of developmental processes to the evolution of neuronal circuits, given that both systems are derived from the ancestral octavolateral column. In particular, to what extent are the respective ITD circuits de novo innovations for processing sound localisation, or a convergent assemblage based on a similar repertoire of ancestral neurons?

To answer these questions, we perform a comparative analysis of the developmental origin of vestibular and hindbrain nuclei. We have exploited recent advances in genetic fate-mapping in chick embryos (Green and Wingate, 2014; Kohl et al., 2012) to compare the origins of avian vestibular and auditory neurons with that recently characterised in mouse (Di Bonito et al., 2013; Di Bonito et al., 2017; Farago et al., 2006; Fujiyama et al., 2009; Marrs and Spirou, 2012; Pasqualetti et al., 2007; Yamada et al., 2007). Specifically we have studied the rhombic lip lineage, characterised by a progenitor pool expressing Atoh1 (Ben-Arie et al., 2000; Machold and Fishell, 2005; Rose et al., 2009; Wang et al., 2005), and a ventricular zone lineage whose precursors express Ptf1a (Meredith et al., 2009; Yamada et al., 2007). These two lineages collectively define the majority of the auditory circuit in mouse, including all first order auditory neurons (Fujiyama et al., 2009). To underpin the Atoh1 and Ptf1a lineage contributions to avian hindbrain vestibular and auditory nuclei we performed an electroporation-based fate-mapping in chick embryos, using enhancer driven reporter constructs. Additionally, we traced their axial origin through the electroporation of reporter constructs driven by enhancer elements from Egr2 (Krox20), Hoxb1, Hoxa3 and Hoxd4.

Our results lend strong support to the hypothesis that vestibular nuclei are developmentally homologous in chick and mouse to a fine level of detail, reflecting the ancestral origin and conservation of these hindbrain structures. By contrast, auditory nuclei show a mixture of conserved and divergent developmental origin. In particular, functionally analogous circuit components in the ITD circuit of the chick and mouse have different lineage contributions supporting a long-held hypothesis that they represent an example of evolutionary convergence.

In order to determine the developmental origin of hindbrain auditory and vestibular nuclei, we performed in ovo electroporation of chick embryos at stages 12 to 14 (Figure 2A) with two contrasting sets of conditional reporter constructs. First, we used enhancer elements from the bHLH transcription factors Atoh1 (Helms et al., 2000; Kohl et al., 2012) and Ptf1a (Meredith et al., 2009), which are expressed in distinct dorsoventrally located neuronal progenitors (Figure 2B). Electroporation with Atoh1-Cre + Flox-pA-GFP + CAGGS-mCherry (Figure 2C) or Ptf1a-Cre + PBase + Pb-Flox-pA-GFP + CAGGS-mCherry (Figure 2D) resulted in broad expression of mCherry and specific GFP labelling of cells located at the Atoh1⁺ rhombic lip or more ventrally located stripes of Ptf1a⁺ progenitors, respectively. The expression of Atoh1 and Ptf1a revealed by in situ hybridisation (Figure 2B) was faithfully recapitulated by the enhancer-driven GFP expression from the reporter constructs (Figure 2C,D). Second, we used enhancer elements from four transcription factors whose expression maps onto segmental boundaries of the early, rhombomeric hindbrain: Egr2 (Krox20), Hoxb1, Hoxa3 and Hoxd4. The expression pattern of the segmental markers was recapitulated by the reporter constructs employed. An Egr2 enhancer element directed GFP expression to r3 and r5 (Chomette et al., 2006); a Hoxb1 enhancer element directed GFP expression to r4 (Ferretti et al., 2005); a Hoxa3 enhancer element directed GFP expression to r5 and r6 (Manzanares et al., 2001) and finally a Hoxd4 enhancer element directed GFP expression caudal to the r6/r7 boundary (Morrison et al., 1997) (Figure 2E).

Figure 2

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To achieve a comprehensive anatomical identification of hindbrain structures, electroporated embryos were incubated to embryonic day 10 (E10) and the distribution of cells within hindbrain nuclei assessed in coronal cryosections. All structures were identified based on the fluorescent signal from the electroporated constructs, nuclear counterstaining and in reference to Nissl stained sections of equivalent orientation and stage (Figure 3A). Fluorescent label was contrasted to Nissl derived templates (Figure 3B) to identify nuclear boundaries on the basis of cytoarchitecture.

Figure 3

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Ptf1a and Atoh1 lineages contribute distinct neuronal populations to hindbrain vestibular nuclei

The vestibular nuclear complex extends rostro-caudally along the entire dorsal hindbrain. Six vestibular nuclei are commonly recognised in birds: superior, Deiters dorsal, Deiters ventral, tangential, medial and descending (Wold, 1976). Vestibular neuronal groups are also defined in terms of a repertoire of projection patterns (such as vestibulo-ocular, vestibulo-spinal and vestibulo-cerebellar) that are common to all vertebrates (Pasqualetti et al., 2007; Straka and Baker, 2013; Straka et al., 2002). However, neurons projecting to different targets are usually intermingled within a given nucleus or span more than one nucleus (Büttner-Ennever, 1992; Daz and Puelles, 2003; Di Bonito et al., 2015; Pétursdóttir, 1990). Accordingly, the different vestibular nuclei are comprised of highly heterogeneous neuronal populations. With the exception of the tangential nucleus, all the vestibular nuclei in birds have a homologous counterpart in vertebrates (Straka and Baker, 2013).

The Superior Vestibular Nucleus (VeS) is the most rostral of the vestibular nuclei and has a heterogeneous complement of cells (Wold, 1976). Electroporation with Atoh1-Cre + Flox-pA-GFP (Atoh1::GFP) resulted in scattered labelling of cells in the VeS, with diverse morphology (Figure 4A). Electroporation with Egr2-Cre + PBase + Pb-Flox-pA-GFP (Egr2::GFP) also labelled diverse VeS neurons (Figure 4B) that are most likely derived exclusively from r3, as r5-derived territory lies considerably caudal to the nucleus, with no labelled cells found in the intervening, presumably r4 derived, territory. Upon electroporation with Hoxb1-Cre + PBase + Pb-Flox-pA-GFP (Hoxb1::GFP), we observed a small number of isolated Hoxb1⁺ cells in the VeS (Figure 4C - arrowheads). The rhombic lip and axial origin of VeS cells is summarised in Figure 4D.

Figure 4

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The morphologically distinct Nucleus Deiters Ventralis (Dv) and Nucleus Deiters Dorsalis (Dd) are characterised by the presence of giant cells, amidst a collection of smaller cells of diverse morphologies (Wold, 1976). Electroporation with Atoh1::GFP resulted in abundant labelling of cells in the Dd and more scattered labelling in the Dv (Figure 4E). Giant, oval cells of the Dd were not observed labelled with Atoh1::GFP, while a single giant multipolar Dv cell was labelled with Atoh1::GFP in only one occasion, in contrast with more frequent labelling of smaller cells (Figure 4F). Electroporation with Ptf1a-Cre + PBase + Pb-Flox-pA-GFP (Ptf1a::GFP) also resulted in abundant labelling of cells in the Dd and Dv (Figure 4G), including numerous small cells (Figure 4H – top panel, arrowheads), that showed a different morphology to the characteristic Dd giant oval cells (Figure 4H – top panel, asterisks), and medium/small size cells in the Dv (Figure 4H – bottom panel, arrowheads).

Axial markers allocated the origin of the Deiters nuclei to the middle hindbrain rhombomeres. Electroporation with Egr2::GFP resulted in scattered labelling of Dd (Figure 4I – left panel) and Dv (Figure 4I – right panel) cells, none of which showed morphological features of giant cells. Electroporation with Hoxb1:: GFP also resulted in labelling of cells in the Dd and Dv, showing a wider range of morphologies, including giant oval cells in the Dd (Figure 4J – left panel) and giant multipolar cells in the Dv (Figure 4J – right panel). In summary, both Atoh1 and Ptf1a progenitors from r3-r5 gave rise to cells in the dorsal and ventral Deiter’s nuclei (Figure 4D). The distinct giant cells appeared to originate from r4 progenitors that may not correspond to either Atoh1⁺ or Ptf1a⁺ lineages.

The Nucleus Tangentialis (Ta) is composed of elongated cells that are located tangential to the incoming VIIIth nerve fibres (Wold, 1976). Electroporation with Atoh1::GFP did not label cells in the Ta (Figure 4K), while Ptf1a::GFP labelling showed only scattered small cells in the Ta territory, none of which corresponded to the characteristic elongated Ta cells (Figure 4L). The latter were labelled by electroporation with Egr2::GFP (Figure 4M), Hoxb1::GFP (Figure 4N) and Hoxa3-Cre + PBase + Pb-Flox-pA-GFP (Hoxa3::GFP) (Figure 4O), indicating they may derive from Atoh1^-/Ptf1a^-negative precursors from r4-r6 (Figure 4D).

The Medial Vestibular Nucleus (VeM) is located beneath the ventricular surface and closely associated with the auditory NM. Contralaterally projecting NM axons divide the VeM into dorsomedial and ventrolateral parts (Figure 5A). Electroporations with Atoh1::GFP showed scattered labelling of VeM cells (Figure 5A and inset), including neurons embedded within the NM fibre tract (Figure 5A – arrow). Electroporation with Ptf1a::GFP revealed abundant Ptf1a derived neurons in both parts of the nucleus (Figure 5B). The VeM has the longest rostrocaudal extent of all the vestibular nuclei (Wold, 1976). Egr2::GFP electroporations labelled numerous cells in the rostral VeM (Figure 5C- left panel), and only scattered cells more caudally, at the level adjacent to the rostral NM (Figure 5C – right panel, arrowheads). VeM cells at this axial level were also labelled via electroporation with Hoxb1 (Figure 5D) and Hoxa3 (Figure 5E) reporter constructs, whilst the middle and caudal VeM was mainly labelled by Hoxd4-Cre + PBase + Pb-Flox-pA-GFP (Hoxd4::GFP) electroporations (Figure 5F). In summary, VeM cells were observed originating from Atoh1⁺ and Ptf1a⁺ progenitors spanning from r3 to axial levels caudal to r7 (Figure 5G).

Figure 5

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The Descending Vestibular Nucleus (VeD) extends rostrocaudally from the level of the VIIIth nerve root to the caudal end of the hindbrain (Wold, 1976). Electroporation with Atoh1::GFP resulted in profuse labelling of neurons in the caudal VeD (Figure 5H) and more scattered cell labelling in the rostral portion of the nucleus, through which NL axons course into the ventral hindbrain and SON axons reach the NL (Lachica et al., 1994; Takahashi and Konishi, 1988) (Figure 5I). Electroporations with Ptf1a::GFP resulted in labelling of small cells throughout the VeD (Figure 5J). The rostral portion of the VeD showed cells labelled via electroporation with Egr2::GFP (Figure 5K) and Hoxa3::GFP (Figure 5L). In turn, the middle and caudal portions of the VeD were labelled by electroporation with Hoxd4::GFP (Figure 5M). Finally, electroporations with Hoxb1::GFP labelled scattered cells in the rostral VeD (Figure 5N), which may have migrated caudally from r4. In summary, our characterisation of the VeD showed cells arising from both Atoh1 and Ptf1a progenitors that span r4 to levels caudal to r7 (Figure 5G).

Avian hindbrain first order auditory nuclei are defined by axially distinct pools of Atoh1 and Ptf1a precursors

In birds, primary auditory afferents synapse at the Nucleus Magnocellularis (NM) and Nucleus Angularis (NA) (Ryugo and Parks, 2003). NM neurons, characterised by their bifurcating ipsilateral and contralateral projections, are labelled by electroporation with Atoh1::GFP (Figure 6A). Ipsilateral axonal projections from NM neurons were observed surrounding the lateral border of the NM on their way towards the Nucleus Laminaris (NL) and terminating on its dorsal region (Figure 6B). At the contralateral (non-electroporated) side, NM axons were observed contacting the ventral side of NL neurons (Figure 6C). At its caudal end, the border between NM and the Descending Vestibular Nucleus (VeD) is difficult to distinguish (Figure 6D). No Ptf1a labelled neurons were found within the NM upon electroporation with Ptf1a::GFP (Figure 6E).

Figure 6

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Electroporation with Egr2::GFP (Figure 6F) and Hoxa3::GFP (Figure 6G) resulted in scattered labelling of NM cells, arising from r5 and r6. Electroporation with Hoxb1::GFP labelled cells in the NM area, but not Atoh1⁺ NM neurons, labelled with Atoh1-Gal4 + UAS-tdT (Atoh1::tdT) (Figure 6H). Finally, electroporation with Hoxd4::GFP resulted in abundant labelling of NM cells (Figure 6I). This caudal rhombic lip origin of NM cells was confirmed via a transectional labelling strategy, wherein electroporation with Hoxd4-Cre + Atoh1-FLPo + Flox/FRT-Flox-pA-GFP + CAG-mCherry resulted in GFP expression after double Cre/FLp recombination driven by Hoxd4 and Atoh1 enhancer elements (Figure 6J). The rhombic lip and axial origin of NM cells is summarised in Figure 6K.

The Nucleus Angularis (NA) is composed of at least four morphologically and electrophysiologically distinct neuronal types: radial, vertical, stubby and planar cells (Soares and Carr, 2001; Soares et al., 2002). Electroporation with Atoh1::GFP resulted in extensive labelling of NA neurons (Figure 6L), that showed morphologies indicative of radial, vertical and planar cells (Figure 6M). Electroporation with Ptf1a::GFP resulted in more scattered labelling of the NA. Ptf1a⁺ NA cells had the distinctive spiny morphology of stubby cells (Figure 6N). Planar, radial and vertical cells (likely Atoh1), but not stubby (likely Ptf1a) cells, were labelled following electroporation with Egr2::GFP (Figure 6O). By contrast, all four cell types were labelled by Hoxb1::GFP electroporations (Figure 6P). This suggests that, while Atoh1⁺ NA cells derived from r3, r4 and r5 (and this may include vertical, planar and radial morphological types), only r4 Ptf1a⁺ progenitors gave rise to NA stubby cells (Figure 4K).

In summary, we observed that the Atoh1 and Ptf1a electroporations labelled all the described cell types in the avian first order hindbrain auditory nuclei. While the axial origin of NA cells was located towards the more rostral rhombomeres, NM cells were observed arising from the caudal rhombic lip (Figure 6K).

The Atoh1 positive rhombic lip is a main source of avian hindbrain second order auditory neurons

In chick, the Nucleus Laminaris (NL) and Superior Olivary Nucleus (SON) comprise the hindbrain second order neuronal populations. They receive input from the NA and NM and are involved in the processing of monaural and binaural auditory cues (Carr and Soares, 2002). The NL sits ventral to the NM and is composed of neurons aligned on a plane along the mediolateral axis. Electroporation with Atoh1::GFP resulted in strong labelling of NL neurons (Figure 7A) that reveals their characteristic bipolar dendritic morphology (Figure 7A - inset), with segregated dorsal and ventral dendrites.

Figure 7

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Electroporations with Egr2::GFP resulted in the two distinct bands of GFP expression corresponding to r3 and r5. Cells of the NL were observed in the caudal band of GFP expression (Figure 7B) suggesting they originated from progenitors in r5, but not r3. NL cells were also labelled by electroporation with Hoxb1::GFP (Figure 7C) and Hoxa3::GFP (Figure 7D), indicating NL neurons derived from r4-r6 progenitors as summarised in Figure 7E. No Ptf1a labelled neurons were found within the NL.

The SON is located in the ventrolateral hindbrain (Figures 3 and 7F). Electroporation with Atoh1::GFP resulted in extensive labelling of SON neurons (Figure 7F). By contrast, electroporation with Ptf1a::GFP only occasionally labelled one or two small cells in the nucleus (Figure 7G - arrowhead).

Electroporation with Egr2::GFP resulted in extensive labelling of SON neurons (Figure 7H). Co-labelling with Egr2::GFP and Atoh1::tdT showed both Egr2⁺/Atoh1^- and Egr2^-/Atoh1⁺ cells, as well as many double labelled Egr2⁺/Atoh1⁺ cells (Figure 7I). This suggested that, within r5, Atoh1⁺ progenitors are not the exclusive source of SON neurons. In addition, electroporation with Hoxb1::GFP (Figure 7J) and Hoxa3::GFP (Figure 7K) labelled scattered cells in the SON, suggesting a small contribution from both r4 and r6 to the predominantly r5 derived SON (Figure 7E).

In summary, both second order auditory nuclei originated from mid-hindbrain progenitors, namely, r4 to r6. The NL, composed of only one cell type, was labelled by Atoh1 electroporation, indicating that it is derived from rhombic lip progenitors. In contrast, the SON is a more heterogeneous nucleus. Accordingly, we observed cells that originated from both Atoh1⁺ and Atoh1^- progenitors. While the latter may include cells of Ptf1a origin, these most likely originated from other progenitor populations.

In this study, we have mapped the rhombic lip/Atoh1, ventricular zone/Ptf1a and axial origin of chick hindbrain vestibular and auditory nuclei. This shows, for the first time, the origins of both systems by rhombomeric identity and specific dorsoventral lineage. Our data give a solid framework by which to assess divergence and convergence within hindbrain functional circuits in birds and mammals. We evaluate the contribution of changes in hindbrain development to the evolution of neuronal circuits, within the context of disparaging evolutionary histories of the different amniote vestibular and auditory structures.

Anatomical, morphological and developmental features indicate a high degree of conservation of hindbrain vestibular nuclei across vertebrates

Vestibular peripheral organs, hindbrain vestibular nuclei and their connectivity patterns are highly conserved across vertebrates and clear evolutionary relationships can be established (Straka and Baker, 2013). The axial developmental origin and location of vestibular neurons projecting to oculomotor, spinal cord, cerebellar and commissural targets are also conserved (Branoner et al., 2016; Chagnaud et al., 2017; Malinvaud et al., 2010; Straka and Baker, 2013; Straka et al., 2014), however, a comparative analysis of the dorsoventral lineage of hindbrain vestibular neurons has been lacking. Here, we show that in chick, cells derived from rhombic lip Atoh1⁺ progenitors were present in the Superior, Deiters, Medial and Descending vestibular nuclei, while we observed no contribution from this lineage to the avian exclusive Tangential nucleus (Figures 4 and 5). Moreover, we have identified cells derived from Ptf1a⁺ progenitors in the Deiters, tangential, medial and descending vestibular nuclei (Figures 4 and 5). These results are similar to fate maps in mouse showing that rhombic lip Atoh1⁺ progenitors contribute to the superior (Wang et al., 2005), lateral, medial and spinal vestibular nuclei (Rose et al., 2009), while Ptf1a⁺ progenitors give rise to vestibular hindbrain neurons, possibly located in all four nuclei (Yamada et al., 2007). Of note, Atoh1 and Ptf1a cells do not account for the whole diversity of cell types, in either chick or mouse (Figure 8), and further mapping efforts are required to fully characterise the genetic lineages that give rise to the myriad of hindbrain vestibular neurons.

Figure 8

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Our high resolution electroporation-based labelling allowed for a detailed characterisation of the axial origin of vestibular neuronal types (Figure 8). The Nucleus Deiters Ventralis (Dv) and Nucleus Deiters Dorsalis (Dd) of birds are homologous to the rostroventral and dorsocaudal part of the mammalian lateral vestibular nucleus, respectively (Passetto et al., 2008), which is mainly derived from r4 progenitors (Chen et al., 2012; Di Bonito et al., 2015), with additional contribution from r3 and r5 (Pasqualetti et al., 2007). Here, we observed a similar axial origin for both the Dv and Dd, with progenitors allocated to r3, r4 and r5 (Figures 4I,J and 8). Moreover, Dv and Dd giant cells derived from Hoxb1⁺ (r4) progenitors. These may constitute a homologous cell type to the r4 derived large stellate cells of the murine lateral (and medial) vestibulospinal tract (Di Bonito et al., 2015; Di Bonito et al., 2017). Finally, we observed a minor group of small r4 derived cells that integrate into the VeS and VeM, invading r3 and r5 derived territories, respectively (Figures 4B and 5 D). A similar group of cells has been described in mouse (Di Bonito et al., 2017) and shown to also belong to the highly conserved vestibulospinal tract. Taken together, these observations support a homologous axial and dorso-ventral origin for spinal cord projecting neurons from both species and highlight the high degree of conservation in the detailed organisation of the ancestral vestibulospinal tract (Straka and Baker, 2013).

Images included in Figures 2-7 are representative of all the data generated and analysed during this study.

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Author details

1. Marcela Lipovsek

   Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Formal analysis, Funding acquisition, Investigation, Visualization, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   marcela.lipovsek@kcl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9328-0328

2. Richard JT Wingate

   1. Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
   2. MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1662-6097

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