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Development of the Serotonergic Cells in Murine Raphe Nuclei and Their Relations with Rhombomeric Domains

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Development of the Serotonergic Cells in Murine Raphe Nuclei and Their Relations with Rhombomeric Domains Brain Struct Funct DOI 10.1007/s00429-012-0456-8 ORIGINAL ARTICLE Development of the serotonergic cells in murine raphe nuclei and their relations with rhombomeric domains Antonia Alonso • Paloma Mercha´n • Juan E. Sandoval • Luisa Sa´nchez-Arrones • Angels Garcia-Cazorla • Rafael Artuch • Jose´ L. Ferra´n • Margaret Martı´nez-de-la-Torre • Luis Puelles Received: 2 August 2012 / Accepted: 8 September 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com Abstract The raphe nuclei represent the origin of central conventional seven raphe nuclei among these twelve units. serotonergic projections. The literature distinguishes seven To this aim, we correlated 5-HT-immunoreacted neurons nuclei grouped into rostral and caudal clusters relative to with rhombomeric boundary landmarks in sagittal mouse the pons. The boundaries of these nuclei have not been brain sections at different developmental stages. Further- defined precisely enough, particularly with regard to more, we performed a partial genoarchitectonic analysis of developmental units, notably hindbrain rhombomeres. We the developing raphe nuclei, mapping all known seroto- hold that a developmental point of view considering nergic differentiation markers, and compared these results, rhombomeres may explain observed differences in con- jointly with others found in the literature, with our map of nectivity and function. There are twelve rhombomeres serotonin-containing populations, in order to examine characterized by particular genetic profiles, and each regional variations in correspondence. Examples of develops between one and four distinct serotonergic pop- regionally selective gene patterns were identified. As a ulations. We have studied the distribution of the result, we produced a rhombomeric classification of some 45 serotonergic populations, and suggested a correspond- A. Alonso Á J. L. Ferra´n Á M. Martı´nez-de-la-Torre Á ing modified terminology. Only a minor rostral part of the L. Puelles (&) dorsal raphe nucleus lies in the midbrain. Some seroto- Department of Human Anatomy and Psychobiology, nergic neurons were found in rhombomere 4, contrary to Faculty of Medicine, School of Medicine, the conventional assumption that it lacks such neurons. We University of Murcia, 30071 Murcia, Spain e-mail: [email protected] expect that our reclassification of raphe nuclei may be useful for causal analysis of their differential molecular P. Mercha´n specification, as well as for studies of differential connec- Division of Developmental Biology, Cincinnati Children’s tivity and function. Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA Keywords Hindbrain Á Rhombomeres Á Serotonin Á J. E. Sandoval Midbrain Á Pet1 Á Lmx1b Institute du Thorax, Universite´ de Nantes, UMR, 1087 Nantes, France Abbreviations L. Sa´nchez-Arrones 4v Fourth ventricle Centro de Biologı´a Molecular Severo Ochoa, CSIC-Universidad 5C Motor trigeminal nucleus, caudal part Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain 5n Trigeminal nerve A. Garcia-Cazorla Á R. Artuch 5R Motor trigeminal nucleus, rostral part Neuropediatrics and Clinical Biochemistry Departments, 7n Facial nerve Hospital Sant Joan de De´u, Barcelona, Spain 8n Vestibulocochlear nerve 10n Vagus nerve A. Garcia-Cazorla Á R. Artuch Biomedical Network of Research Centres on Rare Diseases 11n Accessory nerve (CIBER-ER), Instituto de Salud Carlos III, Madrid, Spain Amb Ambiguus nucleus 123 Brain Struct Funct Cb Cerebellum r1 Rhombomere 1 CLi Caudal linear nucleus of the raphe r1c Caudal part of rhombomere 1 CLiW Caudal linear nucleus of the raphe, lateral wing r1DR r1 part of dorsal raphe nucleus Cu Cuneate nucleus r1DRd r1 part of dorsal raphe nucleus, dorsal part DR Dorsal raphe nucleus r1DRv r1 part of dorsal raphe nucleus, ventral part DTg Dorsal tegmental nucleus r1DRW r1 part of dorsal raphe nucleus, lateral wing ECu External cuneate nucleus r1r Rostral part of rhombomere 1 Gu Gustatory nucleus r2 Rhombomere 2 Gr Gracile nucleus r3 Rhombomere 3 H Hindbrain r3PnR r3 part of pontine raphe nucleus ICo Inferior colliculus r4 Rhombomere 4 III Oculomotor nucleus r4PnR r4 part of pontine raphe nucleus IO Inferior olivary nucleus r5 Rhombomere 5 IPA Interpeduncular nucleus, apical subnucleus r5RMgD r5 part of raphe magnus nucleus, dorsal part IPC Interpeduncular nucleus, caudal subnucleus r5RMgV r5 part of raphe magnus nucleus, ventral part IPPro Interpeduncular nucleus, prodromal subnucleus r5SGeR r5 part of supragenual raphe nucleus IPR Interpeduncular nucleus, rostral subnucleus r6 Rhombomere 6 Is Isthmus r6RMgD r6 part of raphe magnus nucleus, dorsal part isDR Isthmic part of dorsal raphe nucleus r6RMgV r6 part of raphe magnus nucleus, ventral part isDRd Isthmic part of dorsal raphe nucleus, dorsal part r6SGeR r6 part of supragenual raphe nucleus isDRl Isthmic part of dorsal raphe nucleus, lateral part r7 Rhombomere 7 isDRv Isthmic part of dorsal raphe nucleus, ventral part r8 Rhombomere 8 isDRW Isthmic part of dorsal raphe nucleus, lateral wing r9 Rhombomere 9 IV Trochlear nucleus r10 Rhombomere 10 LC Locus coeruleus r11 Rhombomere 11 LLV Ventral nucleus of the lateral lemniscus R Red nucleus LRt Lateral reticular nucleus Rbd Rhabdoid nucleus LVe Lateral vestibular nucleus RMg Raphe magnus nucleus M Midbrain RMgD Raphe magnus nucleus, dorsal part m2 Mesomere 2 (preisthmic midbrain) RMgV Raphe magnus nucleus, ventral part mDR Dorsal raphe nucleus, preisthmic ROb Raphe obscurus nucleus mesencephalic part RPa Raphe pallidus nucleus mesV Mesencephalic trigeminal nucleus RtTg Reticular tegmental nucleus of the pons MHB Midbrain–hindbrain boundary Sag Nucleus sagulum mlf Medial longitudinal fasciculus SC Spinal cord MnR Median raphe nucleus SCo Superior colliculus MnRc Median raphe nucleus, caudal part SGeR Supragenual raphe nucleus MnRr Median raphe nucleus, rostral part SO Superior olive MVe Medial vestibular nucleus Sol Nucleus of the solitary tract my Myelomere Sp5C Spinal trigeminal nucleus, caudal part PB Parabigeminal nucleus Sp5I Spinal trigeminal nucleus, interpolar part PBr Parabrachial nucleus Sp5O Spinal trigeminal nucleus, oral part PDTg Posterodorsal tegmental nucleus SpVe Spinal vestibular nucleus PMB Pontomedullary boundary SuL Supralemniscal raphe complex Pn Pontine nuclei Tz Trapezoid body PnR Pontine raphe nucleus Ve Vestibular nucleus PO Periolivary area VI Abducens nucleus PPnR Prepontine raphe nucleus VII Facial nucleus PPy Parapyramidal raphe complex X Vagal dorsal motor nucleus Pr5C Principal sensory trigeminal nucleus, caudal part XI Accessory nucleus Pr5R Principal sensory trigeminal nucleus, rostral part XII Hypoglossal nucleus py Pyramidal tract xpn Pontine decussation 123 Brain Struct Funct xpy Pyramidal decussation group of parapyramidal serotonergic neurons can be xscp Decussation of the superior cerebellar peduncle added. xtz Trapezoid body decussation Our present aim is to advance a complete rhombomeric classification of raphe nuclei, expecting that this may help causal neuromeric analysis of shared and differential aspects of their molecular specification and differentia- Introduction tion. Our approach suggests a modified terminology that contemplates such developmental ascription (Table 1; Serotonergic neurons associated to raphe nuclei are Fig. 1b). In our analysis, apart of attending to literature represented throughout the hindbrain and nowhere else data on genoarchitecture, fate mapping (Marı´n and Pu- in the brain (with the exception of minor midbrain and elles 1995; Cambronero and Puelles 2000) and rhombo- spinal additions). Nieuwenhuys (1985) reviewed litera- mere-related lineage mapping (Jensen et al. 2008), we ture showing that this cell type normally coexists in essentially followed the rhombomere schema of the Allen these nuclei with other sorts of neurons, in variable Developing Mouse Brain Atlas (http://developingmouse. proportions. In fact, a retropontine ‘nucleus raphe in- brain-map.org/), whose reference atlases indicating terpositus’ is mentioned in the literature that holds no rhombomeric units at different stages oriented our inter- serotonergic neurons at all (Bu¨ttner-Enever et al. 1998). pretation (note these reference atlases were elaborated by In the present work we concentrate on the serotonergic LP; see similar use by Watson and Paxinos 2010). Such populations. mapping is relatively straightforward and reproducible, We now know that the hindbrain is organized devel- due to the abundance of known neuromeric landmarks. A opmentally in a series of transverse neuromeric units, further point of interest was to check whether the generically named rhombomeres (Puelles et al. 2007; molecular profile of developing raphe populations is Nieuwenhuys et al. 2008;Nieuwenhuys2011;Watson uniform along the diverse hindbrain neuromeric units, or and Paxinos 2010). It can be deduced from known shows some regional differences, irrespective of the descriptions that each rhombomere probably produces a development of a common neurotransmitter phenotype. specific part of the series of raphe nuclei, but the corre- To this end, we mapped comparatively in sagittal sections sponding distribution has not been determined yet. at critical developmental stages diverse gene markers Recently, Jensen et al. (2008) used triple transgenic previously associated to specification of the serotonergic mappings to locate serotonergic populations derived, neuronal phenotype (En1, En2, Gata2, Gata3, Lmx1b, respectively, from r1, r2, r3 and
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