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• W2001347360 abstract "The cochlear nuclear complex (CN) is the entry point for central auditory processing. Although constituent neurons have been studied physiologically, their embryological origins and molecular profiles remain obscure. Applying intersectional and subtractive genetic fate mapping approaches, we show that this complex develops modularly from genetically separable progenitor populations arrayed as rostrocaudal microdomains within and outside the hindbrain (lower) rhombic lip (LRL). The dorsal CN subdivision, structurally and topographically similar to the cerebellum, arises from microdomains unexpectedly caudal and noncontiguous to cerebellar primordium; ventral CN subdivisions arise from more rostral LRL. Magnocellular regions receive contributions from LRL and coaxial non-lip progenitors; contrastingly, ensheathing granule cells derive principally from LRL. Also LRL-derived and molecularly similar to CN granule cells are precerebellar mossy fiber neurons; surprisingly, these ostensibly intertwined populations have separable origins and adjacent but segregated migratory streams. Together, these findings provide new platforms for investigating the development and evolution of auditory and cerebellar systems. The cochlear nuclear complex (CN) is the entry point for central auditory processing. Although constituent neurons have been studied physiologically, their embryological origins and molecular profiles remain obscure. Applying intersectional and subtractive genetic fate mapping approaches, we show that this complex develops modularly from genetically separable progenitor populations arrayed as rostrocaudal microdomains within and outside the hindbrain (lower) rhombic lip (LRL). The dorsal CN subdivision, structurally and topographically similar to the cerebellum, arises from microdomains unexpectedly caudal and noncontiguous to cerebellar primordium; ventral CN subdivisions arise from more rostral LRL. Magnocellular regions receive contributions from LRL and coaxial non-lip progenitors; contrastingly, ensheathing granule cells derive principally from LRL. Also LRL-derived and molecularly similar to CN granule cells are precerebellar mossy fiber neurons; surprisingly, these ostensibly intertwined populations have separable origins and adjacent but segregated migratory streams. Together, these findings provide new platforms for investigating the development and evolution of auditory and cerebellar systems. Essential to normal sound recognition is the proper development of the auditory processing centers in the peripheral and central nervous systems. All auditory information, relayed by spiral ganglion neurons of the inner ear, coalesces in a tonotopic distribution upon the hindbrain neuronal densities known as the cochlear nuclei (reviewed in Ryugo and Parks, 2003Ryugo D.K. Parks T.N. Primary innervation of the avian and mammalian cochlear nucleus.Brain Res. Bull. 2003; 60: 435-456Crossref PubMed Scopus (90) Google Scholar). This critical complex has been studied extensively with respect to its diverse neuronal cell types, its unique synaptic morphologies and circuitries, and its physiological role in auditory processing (reviewed in Cant, 1992Cant N.B. The Cochlear Nucleus: Neuronal Types and Their Synaptic Organization.in: Webster D.B. Popper A.N. Fay R.R. The Mammalian Auditory Pathway: Neuroanatomy. Springer-Verlag, New York1992: 66-116Crossref Google Scholar). Less well understood are the embryological origins, gene expression histories, and molecular profiles of the constituent cells. In this study, we apply in mice an intersectional and subtractive genetic fate mapping approach toward addressing these fundamentals. Genetic fate mapping strategies in mice involving site-specific recombinases have proven to be of great value to the developmental neurobiologist, complementing and extending other more classical lineage and grafting methods that have been employed largely in avian systems. Because genetic fate maps delineate adult structures and cell types arising from molecularly defined subsets of embryonic cells, they not only inform developmental processes but also guide analyses of mouse mutants. The impact of these approaches is evidenced by a set of recent studies directed at cerebellar and brainstem development (Awatramani et al., 2003Awatramani R. Soriano P. Rodriguez C. Mai J.J. Dymecki S.M. Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation.Nat. Genet. 2003; 35: 70-75Crossref PubMed Scopus (155) Google Scholar, Landsberg et al., 2005Landsberg R.L. Awatramani R.B. Hunter N.L. Farago A.F. Dipietrantonio H.J. Rodriguez C.I. Dymecki S.M. Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by pax6.Neuron. 2005; 48: 933-947Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Machold and Fishell, 2005Machold R. Fishell G. Math1 is expressed in temporally discrete pools of cerebellar rhombic-lip neural progenitors.Neuron. 2005; 48: 17-24Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, Rodriguez and Dymecki, 2000Rodriguez C.I. Dymecki S.M. Origin of the precerebellar system.Neuron. 2000; 27: 475-486Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, Sgaier et al., 2005Sgaier S.K. Millet S. Villanueva M.P. Berenshteyn F. Song C. Joyner A.L. Morphogenetic and cellular movements that shape the mouse cerebellum; insights from genetic fate mapping.Neuron. 2005; 45: 27-40Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, Zervas et al., 2004Zervas M. Millet S. Ahn S. Joyner A.L. Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1.Neuron. 2004; 43: 345-357Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar) from which unexpected lineage relationships and complex cellular movements have been revealed, in addition to more precise interpretations of loss-of-function phenotypes. Despite the molecular precision afforded by genetic fate maps, many biological questions remain unanswerable because of the broad extent of cell types marked even by a single gene expression domain. Embryonic gene expression domains commonly restrict along one tissue axis but extend along the orthogonal axes, such that a given gene expression domain actually includes a substantial swathe of varied cell populations. Especially constrained by this property have been studies of the hindbrain (lower) rhombic lip (LRL)—a specialized germinal zone productive of long-distance, tangentially migrating neurons (Altman and Bayer, 1996Altman J. Bayer S.A. Development of the Cerebellar System: In Relation to Its Evoultion, Structure, and Functions. CRC Press, Boca Raton, FL1996Google Scholar, Essick, 1912Essick C.R. The development of the nuclei pontis and the nucleus arcuatus in man.Am. J. Anat. 1912; 13: 25-54Crossref Scopus (99) Google Scholar, Harkmark, 1954Harkmark W. Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons; a morphological and experimental investigation on chick embryos.J. Comp. Neurol. 1954; 100: 115-209Crossref PubMed Scopus (142) Google Scholar, His, 1891His W. Die Entwicklung des menschlichen Rautenhirns vom Ende des ersten bis vum Beginn des dritten Monats. I. Verlangertes Mark. Abhandlungen der koniglicher sachsischen Gesellschaft der Wissenschaften.Mathematische-physikalische Klasse. 1891; 29: 1-74Google Scholar, Palay and Chan-Palay, 1974Palay S.L. Chan-Palay V. Cerebellar Cortex: Cytology and Organization. Springer, New York1974Crossref Google Scholar, Taber Pierce, 1966Taber Pierce E. Histogenesis of the nuclei griseum pontis, corporis pontobulbaris and reticularis tegmenti pontis (Bechterew) in the mouse. An autoradiographic study.J. Comp. Neurol. 1966; 126: 219-254Crossref PubMed Scopus (95) Google Scholar; reviewed in Wingate, 2001Wingate R.J. The rhombic lip and early cerebellar development.Curr. Opin. Neurobiol. 2001; 11: 82-88Crossref PubMed Scopus (208) Google Scholar). Among LRL-descendant lineages are the many varied neuron subtypes of the precerebellar afferent system (Rodriguez and Dymecki, 2000Rodriguez C.I. Dymecki S.M. Origin of the precerebellar system.Neuron. 2000; 27: 475-486Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, Landsberg et al., 2005Landsberg R.L. Awatramani R.B. Hunter N.L. Farago A.F. Dipietrantonio H.J. Rodriguez C.I. Dymecki S.M. Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by pax6.Neuron. 2005; 48: 933-947Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar) and at least some constituent neurons of the cochlear nuclear complex (CN) (Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). While LRL territory is restricted to dorsal-most neuroectoderm, it spans the full rostrocaudal extent of the hindbrain from rhombomere (r) 2 through 8. Most dorsally restricted genes expressed specifically in the LRL also span this full rostrocaudal extent (Rodriguez and Dymecki, 2000Rodriguez C.I. Dymecki S.M. Origin of the precerebellar system.Neuron. 2000; 27: 475-486Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar) and therefore lend no rostrocaudal resolution to lineage-specific origins within the LRL. Further hampering analyses is the lack of discriminating molecular markers that can distinguish each LRL sublineage as it emigrates. This is especially critical, as LRL derivatives distribute extensively during development along seemingly entwined paths, making it exceptionally difficult to link final fate to precise originating coordinates within the LRL and the associated molecular programs enacted therein. With respect to the mammalian cochlear nuclear complex, recent data point to the LRL as the source for some constituent neurons (Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar), although their precise rostrocaudal:dorsoventral coordinate position (and therefore molecular profile) of origin within the LRL is not known, nor are the locations of other (non-LRL) contributing progenitors. Unique gene expression profiles distinguish individual rhombomeres (reviewed in Lumsden and Krumlauf, 1996Lumsden A. Krumlauf R. Patterning the vertebrate neuraxis.Science. 1996; 274: 1109-1115Crossref PubMed Scopus (923) Google Scholar) and do so seemingly by encompassing the full dorsoventral extent of a given rhombomere. Thus, even though the LRL, in its production of tangentially migrating cells, is mechanistically distinct from the majority of hindbrain germinative neuroepithelium, it is likely, nevertheless, to be partitioned rostrocaudally by these same rhombomere-specific gene expression profiles. This appears to be the case for at least distinguishing the avian upper rhombic lip of r1 generally from the LRL (r2–r8) (Eddison et al., 2004Eddison M. Toole L. Bell E. Wingate R.J. Segmental identity and cerebellar granule cell induction in rhombomere 1.BMC Biol. 2004; 2: 14Crossref PubMed Scopus (24) Google Scholar, Wingate and Hatten, 1999Wingate R.J. Hatten M.E. The role of the rhombic lip in avian cerebellum development.Development. 1999; 126: 4395-4404PubMed Google Scholar). Thus, it is possible that molecularly distinct progenitor pools are arrayed along the entire rostrocaudal span of the LRL and that the genetic differences characterizing these pools are relevant to specific cochlear and precerebellar fates. To test this possibility in mice, we have developed a high-resolution, dual recombinase-responsive indicator allele that, when coupled with two recombinase-expressing alleles (one encoding Cre and the other Flpe), “intersectionally” tracks lineages defined by a shared history of two gene expression profiles. (Figure 1A, cells cartooned in green). For example, by combining this indicator allele with a LRL-specific Flpe allele and a rhombomere-specific cre allele, only those LRL progenitors at that rhombomeric or axial level are marked by green fluorescent protein (GFP) (Figure 1A, cells colored green). A second feature of this strategy is the ability to simultaneously track “Cre/non-Flp” lineages (Figure 1A, cells colored blue); by “subtracting” away from the Cre-expressing domain those cells arising from the Cre/Flp genetic intersection, the reciprocal more-narrowed subset of Cre-only-expressing cells can be analyzed. By exploiting both features, we have been able to track simultaneously rhombomere-specific LRL lineages (green cells) within the context of other derivatives arising from non-LRL territories within that same rhombomere (blue cells). Thus, this general approach can be exploited in two ways to reduce the complexity and increase the resolution available in genetic fate maps: by an intersectional requirement for defining one subpopulation and a subtractive requirement for defining another. Through application of this strategy, we delineate within the LRL separate rostrocaudal territories encompassing auditory and precerebellar progenitors. We provide evidence that the more rostrally located “auditory lip” distributes neurons throughout the entire brainstem cochlear nuclear complex and is further divisible into microdomains along its rostrocaudal axis in relation to future cochlear nuclei fate—the anteroventral cochlear nucleus (AVCN), the posteroventral cochlear nucleus (PVCN), and the dorsal cochlear nucleus (DCN). Thus, we show that the mammalian LRL is parceled genetically along the rostrocaudal axis into molecularly discrete progenitor pools associated with specific neuronal fates. Using the subtractive feature of this new indicator allele, we have also been able to ascertain contributions to the deep projection regions of each cochlear nucleus from progenitor zones lying ventral to the auditory lip. By contrast, granule cells that ensheath the entire cochlear nuclear complex derive almost entirely from the auditory lip; additionally, they share in part a molecular profile with precerebellar mossy fiber neurons. Remarkably, these two similar populations (cochlear nuclei granule cells and precerebellar neurons) converge topographically during development but do not mix. Unexpectedly, the DCN, the cochlear nucleus adjacent and structurally similar to the cerebellum (reviewed in Oertel and Young, 2004Oertel D. Young E.D. What's a cerebellar circuit doing in the auditory system?.Trends Neurosci. 2004; 27: 104-110Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar), does not arise from LRL territory situated immediately adjacent to the cerebellar primordium in r1; instead, it arises from noncontiguous, more caudal regions of auditory lip. Their juxtaposition in the mature brain is likely secondary to morphogenetic transformations such as those associated with the pontine flexure. These collective findings, made possible only through application of the dual recombinase-responsive indicator allele introduced herein, provide a new foundation for studying auditory and precerebellar development. To map onto specific cell fates either progenitor-specific expression of single genes, gene combinations, or gene subtractions, we generated a novel dual recombinase-responsive indicator allele designed to express nuclear β-galactosidase (nβ-gal) after a Cre-mediated DNA excision and to turn off expression of nβ-gal and turn on expression of a farnesylated (membrane-localized) version of enhanced GFP (eGFPF) (Awatramani et al., 2003Awatramani R. Soriano P. Rodriguez C. Mai J.J. Dymecki S.M. Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation.Nat. Genet. 2003; 35: 70-75Crossref PubMed Scopus (155) Google Scholar, Jiang and Hunter, 1998Jiang W. Hunter T. Analysis of cell-cycle profiles in transfected cells using a membrane-targeted GFP.Biotechniques. 1998; 24: 349-350, 352, 354Crossref PubMed Scopus (65) Google Scholar) along with the lectin wheat germ agglutinin (WGA) (Yoshihara et al., 1999Yoshihara Y. Mizuno T. Nakahira M. Kawasaki M. Watanabe Y. Kagamiyama H. Jishage K. Ueda O. Suzuki H. Tabuchi K. et al.A genetic approach to visualization of multisynaptic neural pathways using plant lectin transgene.Neuron. 1999; 22: 33-41Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar) only after both Flp- and Cre-mediated excisions (Figures 1A and 1B). We refer to this indicator allele as RC::PFwe. Its generation involved targeting to the Gt(ROSA)26Sor (R26) locus (Zambrowicz et al., 1997Zambrowicz B.P. Imamoto A. Fiering S. Herzenberg L.A. Kerr W.G. Soriano P. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells.Proc. Natl. Acad. Sci. USA. 1997; 94: 3789-3794Crossref PubMed Scopus (680) Google Scholar) a CAG (Niwa et al., 1991Niwa H. Yamamura K. Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector.Gene. 1991; 108: 193-199Crossref PubMed Scopus (4424) Google Scholar) driven transgene harboring a loxP- and FRT-disrupted WGA/eGFPF bicistronic transcriptional unit (Figure 1B). Thus, intersectional descendants (Figure 1A, green-colored cells) are marked by expression of both WGA and eGFPF, molecules that permit aspects of cell morphology and axonal projections to be visualized, with WGA offering in limited circumstances the potential to map synaptic partners via specific transneuronal transfer. Cre-descendants lying outside the genetic intersection (Figure 1A, blue-colored cells) are marked by expression of nβ-gal, which through its nuclear localization facilitates identification of individual cells. In triply transgenic animals (Flp, cre, indicator), removal of the nlacZ cassette from intersectional lineages (by Flp-mediated excision) restricts nβ-gal marking to Cre/non-Flp descendants. This subtractive feature permits the reciprocal subset of Cre-only-expressing cells to be mapped. To test the recombinase dependency of reporter expression from the RC::PFwe allele, we analyzed the parental RC::PFwe strain along with the two derivative strains, RC::Fwe and RC::Pwe, generated through germline deletion of either the loxP- or FRT-flanked cassette, respectively (Figure 2A). While RC::PFwe is responsive to both Cre and Flp, FRT-disrupted WGA/eGFPF (RC::Fwe) is responsive only to Flp, and loxP-disrupted WGA/eGFPF (RC::Pwe) only to Cre. We have employed a variety of tissue-specific cre- and Flpe-expressing transgenes with these alleles. As proof of principle, we highlight here results using Wnt1::cre (Chai et al., 2000Chai Y. Jiang X. Ito Y. Bringas Jr., P. Han J. Rowitch D.H. Soriano P. McMahon A.P. Sucov H.M. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis.Development. 2000; 127: 1671-1679Crossref PubMed Google Scholar) and Wnt1::Flpe (Awatramani et al., 2003Awatramani R. Soriano P. Rodriguez C. Mai J.J. Dymecki S.M. Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation.Nat. Genet. 2003; 35: 70-75Crossref PubMed Scopus (155) Google Scholar) transgenes, which mediate recombination in dorsal neural tube progenitors; we show spinal neural tube to illustrate allele features. In the absence of recombination events, nβ-gal, eGFPF, and WGA were all undetectable from the RC::PFwe allele (Figure 2B); eGFPF and WGA were equally undetectable from either the derivative RC::Fwe allele (Figure 2D, middle and lower panels) or the RC::Pwe allele (Figure 2F, middle and lower panels). These findings indicate that the employed “stop” sequences (an SV40 polyadenylation signal sequence [pA] concatamer and separately a bovine growth hormone pA concatamer) were sufficient to prevent detectable levels of reporter expression in the absence of recombination. Following Cre-mediated recombination of RC::PFwe in the dorsal neural tube, progenitors and their progeny (for example, primary sensory dorsal root ganglion neurons [DRGs]) (Figure 2C, black arrowhead) produced nβ-gal but no detectable eGFPF or WGA. The derivative allele RC::Fwe (Figure 2A), in the absence of recombination, was broadly productive of nβ-gal (Figure 2D upper panel); this was expected, given that nlacZ expression from this allele is driven in an unconditional fashion from R26 and CAG regulatory elements. Following Flpe-mediated excision in Wnt1+ cells of the FRT-flanked nlacZ cassette in RC::Fwe, nβ-gal was extinguished in dorsal neural tube progenitors and their progeny (Figure 2E, upper panel); in its place, these cells activated expression of eGFPF and WGA (Figure 2E, middle and lower panels, respectively). Given that Wnt1::Flpe-mediated excision of the nlacZ cassette starts as early as ∼8.5 days post coitum (dpc) and that nβ-gal activity in Wnt1::Flpe descendants is gone by 11.5 dpc (Figure 2E, upper panel), perdurance of nβ-gal following deletion of nlacZ is minimal and nonconfounding. Notably, this short nβ-gal half-life ensures against codetection of nβ-gal in intersectional eGFPF+ descendants (Figure 1A). Such codetection would compromise the resolving power of any intersectional indicator allele when used in subtractive strategies. Importantly, this does not appear to be the case here; rather, when RC::PFwe is used in conjunction with both a cre and Flp allele, nβ-gal is capable of identifying faithfully the Cre/non-Flp lineages. Analyses of Wnt1::Flpe;RC::Fwe double transgenics (Figure 2E) and Wnt1::cre;RC::Pwe double trangenics (Figure 2G) demonstrate the membrane localization of the eGFPF reporter, as evidenced in sensory dendrites extending from DRGs (Figure 2, middle panels in [E] and [G], open arrowheads). Similar morphology was observed on detection of WGA (Figure 2, lower panels in [E] and [G]). In summary, reporter molecule activation from RC::PFwe and its derivative lines was strictly recombinase dependent and yielded the anticipated patterns of expression. Similar results were observed in other regions of the central nervous system and at other time points (data not shown). While incorporation of WGA offers the potential to map not only cell fate but future synaptic partners (Braz et al., 2002Braz J.M. Rico B. Basbaum A.I. Transneuronal tracing of diverse CNS circuits by Cre-mediated induction of wheat germ agglutinin in transgenic mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 15148-15153Crossref PubMed Scopus (79) Google Scholar, Yoshihara et al., 1999Yoshihara Y. Mizuno T. Nakahira M. Kawasaki M. Watanabe Y. Kagamiyama H. Jishage K. Ueda O. Suzuki H. Tabuchi K. et al.A genetic approach to visualization of multisynaptic neural pathways using plant lectin transgene.Neuron. 1999; 22: 33-41Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), in further analyses presented here we exploit only the nβ-gal and eGFPF features of the RC::PFwe allele. The term “lower rhombic lip” (LRL) refers to a spatial and temporal domain of hindbrain neuroepithelium situated at the interface between the roof plate of the fourth ventricle and the neural tube that spans r2–r8 (Figures 3A–3F) (Essick, 1912Essick C.R. The development of the nuclei pontis and the nucleus arcuatus in man.Am. J. Anat. 1912; 13: 25-54Crossref Scopus (99) Google Scholar, Harkmark, 1954Harkmark W. Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons; a morphological and experimental investigation on chick embryos.J. Comp. Neurol. 1954; 100: 115-209Crossref PubMed Scopus (142) Google Scholar, His, 1891His W. Die Entwicklung des menschlichen Rautenhirns vom Ende des ersten bis vum Beginn des dritten Monats. I. Verlangertes Mark. Abhandlungen der koniglicher sachsischen Gesellschaft der Wissenschaften.Mathematische-physikalische Klasse. 1891; 29: 1-74Google Scholar, Palay and Chan-Palay, 1974Palay S.L. Chan-Palay V. Cerebellar Cortex: Cytology and Organization. Springer, New York1974Crossref Google Scholar; reviewed in Wingate, 2001Wingate R.J. The rhombic lip and early cerebellar development.Curr. Opin. Neurobiol. 2001; 11: 82-88Crossref PubMed Scopus (208) Google Scholar) and is mitotically active from ∼10–17 dpc (Altman and Bayer, 1996Altman J. Bayer S.A. Development of the Cerebellar System: In Relation to Its Evoultion, Structure, and Functions. CRC Press, Boca Raton, FL1996Google Scholar, Taber Pierce, 1966Taber Pierce E. Histogenesis of the nuclei griseum pontis, corporis pontobulbaris and reticularis tegmenti pontis (Bechterew) in the mouse. An autoradiographic study.J. Comp. Neurol. 1966; 126: 219-254Crossref PubMed Scopus (95) Google Scholar). We define operationally the dorsoventral (DV) extent of the LRL as Wnt1-expressing territory because it is this region that is productive of tangentially migrating neurons, inclusive of those that migrate extramurally as well as those that migrate intramurally (Landsberg et al., 2005Landsberg R.L. Awatramani R.B. Hunter N.L. Farago A.F. Dipietrantonio H.J. Rodriguez C.I. Dymecki S.M. Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by pax6.Neuron. 2005; 48: 933-947Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Nichols and Bruce, 2005Nichols D.H. Bruce L.L. Migratory routes and fates of cells transcribing the Wnt-1 gene in the murine hindbrain.Dev. Dyn. 2005; 235: 285-300Crossref Scopus (52) Google Scholar, Rodriguez and Dymecki, 2000Rodriguez C.I. Dymecki S.M. Origin of the precerebellar system.Neuron. 2000; 27: 475-486Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar), and therefore in accord with the classical histogenetic definition of the rhombic lip. Progressing dorsoventrally within this Wnt1+ territory reside molecularly separable progenitor pools, for example, as demarcated by Gdf7, Math1, and Ngn1 expression (Landsberg et al., 2005Landsberg R.L. Awatramani R.B. Hunter N.L. Farago A.F. Dipietrantonio H.J. Rodriguez C.I. Dymecki S.M. Hindbrain rhombic lip is comprised of discrete progenitor cell populations allocated by pax6.Neuron. 2005; 48: 933-947Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). Recently, genetic fate maps of the hindbrain Math1 territory have been approximated using β-gal perdurance from a Math1lacZki allele (Wang et al., 2005Wang V.Y. Rose M.F. Zoghbi H.Y. Math1 expression redefines the rhombic lip derivatives and reveals novel lineages within the brainstem and cerebellum.Neuron. 2005; 48: 31-43Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar). Among descendant cell types observed were cochlear granule cells and neurons of the ventral cochlear nuclei (VCN, inclusive of the AVCN and PVCN subdivisions); within the cochlear nuclear complex, very few nβ-gal+ cells were found populating the dorsal cochlear nucleus (DCN). Since Wnt1 is expressed throughout the entire LRL (inclusive of but extending beyond the Math1 subdomain), we first set out to determine the contribution made by the entire LRL to the cochlear nuclear complex, paying special attention to the DCN. To do this, we exploited the Cre-responsive (single recombinase) feature of the RC::PFwe allele. On partnering with a Wnt1::cre transgene (Chai et al., 2000Chai Y. Jiang X. Ito Y. Bringas Jr., P. Han J. Rowitch D.H. Soriano P. McMahon A.P. Sucov H.M. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis.Development. 2000; 127: 1671-1679Crossref PubMed Google Scholar), in which cre recombinase expression mirrors that of endogenous Wnt1 in this region of the brain (Figure 3B versus 3C, 3E versus 3F, and Figure S1), we were able to follow the fate of Wnt1::cre derivatives based on their sustained expression of nβ-gal. Marked cells distributed densely throughout all divisions of the cochlear nuclear complex: the magnocellular cores of the AVCN, PVCN, and DCN (Figures 3H–3J) and the entire microneuronal shell (Figures 3H–3J, white arrows). Coimmunodetection of nβ-gal and the neuron-specific nuclear antigen NeuN indicates that the majority of Wnt1-descendants are indeed neurons (Figures 3H–3J, insets)—although NeuN does not appear to mark all neuronal cell types within the cochlear nuclear complex and therefore underestimates this population. While the LRL generates both cochlear and precerebellar neurons, it remains unclear whether in the mouse these two complex populations emerge from overlapping or distinct axial levels, especially given that precerebellar nuclei such as the pontine gray nucleus (PGN) and inferior olivary nucleus (ION) flank rostrocaudally the cochlear nuclear complex (schematized in Figure 3G). To determine definitively the axial level at which auditory and precerebellar lineages emerge from the LRL, we exploited the intersectional and subtractive" @default.
• W2001347360 created "2016-06-24" @default.
• W2001347360 creator A5000064890 @default.
• W2001347360 creator A5066069221 @default.
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• W2001347360 date "2006-04-01" @default.
• W2001347360 modified "2023-10-11" @default.
• W2001347360 title "Assembly of the Brainstem Cochlear Nuclear Complex Is Revealed by Intersectional and Subtractive Genetic Fate Maps" @default.
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