The PN are predominantly innervated by the cerebral cortex and project as mossy fibers to the cerebellar hemispheres. Here, we comprehensively review the development of the PN from specification to migration, nucleogenesis and circuit formation.
PN neurons originate at the posterior rhombic lip and migrate tangentially crossing several rhombomere derived territories to reach their final position in ventral part of the pons. The developing PN provide a classical example of tangential neuronal migration and a study system for understanding its molecular underpinnings.
We anticipate that understanding the mechanisms of PN migration and assembly will also permit a deeper understanding of the molecular and cellular basis of cortico-cerebellar circuit formation and function. The basal pontine nuclei BPN also known as basilar pons, pontine gray nuclei or pontine nuclei PN and the reticulotegmental nuclei RTN also known as nucleus reticularis tegmenti pontis are located within the ventral portion of the pons. Both nuclei together referred to as PN cannot be distinguished molecularly during development.
The PN constitute the main mossy fiber input to the cerebellum carrying information from the cerebral cortex. The development of the PN has been intensively studied.
Considerable progress has been made in understanding how the stereotypic tangential neuronal migration and positioning of the PN next to the ventral midline of the rhombomere r 3- and 4-derived territory are orchestrated. Also, several studies addressed how the initial steps of axon guidance to the cerebellum and innervation from the cortex are organized.
Yet, our understanding of the mechanisms that pattern the complex input-output circuitry of the PN is limited. Recent studies have shown that the PN are composed of a heterogeneous population of projection neurons and that this diversity might in turn contribute to the complex connectivity between neocortex, PN and cerebellum.
The aim of this review article is to provide an overview of our current understanding of the development of the PN and their circuitry. Moreover, we propose that developmental programs and protomaps established at the pre-migratory stage contribute in shaping the cortico-ponto-cerebellar circuitry.
This is further influenced by environmental factors during migration and nucleogenesis. By summarizing the main literature that attempts to describe the complex input-output connectivity of the PN and their partially topographic organization, we describe emerging concepts on the logic behind the cortico-ponto-cerebellar connectivity. We also speculate about the evolution of PN and the cortico-ponto-cerebellar pathway.
Lastly, we discuss outstanding questions and how they can be approached. Development of rhombic lip derivatives has been intensively studied reviewed in Di Meglio and Rijli, ; Sotelo and Chedotal, ; Hatanaka et al. Precerebellar neuron progenitor pools within the Wnt1 rhombic lip domain are molecularly and spatially defined, giving rise to distinct neuronal populations. All mossy fiber precerebellar neurons, i. The precerebellar nuclei and their specification.
The precerebellar ION is the source of the climbing fibers. B The PN are derived from progenitors at the rhombic lip. The rhombic lip is dorsoventrally patterned. Specified PN neurons migrate in the aes to their final position in the ventral pons. In mouse, the posterior lower rhombic lip precerebellar lip spans rhombomere r 6 to pseudo-rhombomere pr 8 Figures 2A,B.
These rostrocaudal progenitor domains are molecularly defined by the partially overlapping expression of Hox genes of the paralog group 2—5 Hox2—5 whereas they lack Hox6—11 expression Di Meglio et al. More anterior Atoh1 -positive rhombic lip progenitors generate the granule neurons of the cerebellum r1-derived and the neurons of the brainstem cochlear complex r2-r5-derived , respectively Rodriguez and Dymecki, ; Machold and Fishell, ; Wang et al.
The migratory streams of precerebellar neurons. A—D The PN derive from rhombomere r 6—pr8 precerebellar rhombic lip and take a rostroventral path in the AES to finally settle ventrally in r3 partially and in r4 derived territories. Other precerebellar nuclei such as the LRN and ECN derive from pr7—pr8, migrate ventrally in the PES, cross the midline, and settle contralaterally at more dorsal positions.
Migratory streams are shown from lateral A,C and ventral B,D views as schematic drawings A,B and as whole-mount in situ hybridization using the precerebellar neuron marker Barhl1 , as a probe C,D.
Several other transcription factors have been shown to affect the development of the PN and other precerebellar nuclei. Also, PAX6 has been shown to influence the specification of dorso-ventral domains in the rhombic lip by maintaining normal levels of BMP signaling.
Pax6 null mutants have a reduced Atoh1 domain, but an increased Ngn1 domain. Finally, distinct precerebellar nuclei are generated during different ontogenetic periods, as shown initially by tritiated thymidine radiographic studies in the rat Altman and Bayer, d. From the rhombic lip, PN neurons undertake a long-distance tangential migration via the anterior extramural stream AES. In contrast to radial migration, where neurons use radial glia as a scaffold, AES tangentially migrating neurons move orthogonally to the orientation of radial glia, just beneath the meninges.
After leaving r6—pr8, PN neurons migrate ventrally phase I. Next, they turn rostrally and migrate through r5 and r4, passing the vestibulocochlear and facial nerve roots phase 2. The migratory stream then enters r3 and reaches the trigeminal nerve root in the caudal aspect of r2 where it turns again ventrally phase 3 and finally settle on both sides of the floor plate in-between rostral r3 and rostral r5 derived territories Farago et al.
Some PN neurons cross the midline and contribute to the contralateral PN. In mice, the generation, migration, and settlement at final destination of PN neurons takes place between E The migration time of a single neuron from leaving the rhombic lip to reaching its final destination is approximately two days with the last neurons arriving at E18 Okada et al.
In utero electroporation as a tool for analyzing PN development. A—C In utero electroporation of E AES: anterior extramural stream, PN: pontine nuclei. A—C from Kratochwil, Molecular mechanisms controlling migration of pontine neurons I.
In the first phase phase I PN neurons migrate ventrally, switch then to a rostral direction phase II , and finally migrate to the ventral midline phase III. PN: pontine nuclei. Several reasons make the precerebellar system a suitable system for studying tangential migration.
First, the subpial migratory streams can be easily visualized. Cells migrate directly underneath the meninges. Several markers allow to specifically distinguish migrating precerebellar cells from the surrounding tissue, including Barhl1 Figures 2C,D Mbh2 Li et al. Using this approach, it is also possible to efficiently screen for migratory defects in knockout mutant mice.
Also, several Gfp and Cre or Flp recombinase transgenic and knock-in mouse lines are available that target precerebellar neurons facilitating not only the analysis of the migration phenotypes but also allowing conditional knockout targeting of precerebellar neurons Danielian et al.
More recently, in utero electroporation of precerebellar progenitors has become a powerful tool for analyzing the molecular mechanisms of tangential migration Okada et al. Using this approach, not only can migrating neurons be effectively visualized at a single cell resolution by reporter gene expression, but they can also be co-electroporated with genes of interest or RNA interfering constructs for gain-of-function or knockdown experiments, respectively.
PN neurons, as other migrating precerebellar nuclei neurons, are attracted by the floorplate. Molecular mechanisms regulating the migration of pontine neurons II.
A Slits, released from the facial nucleus, repel rostrally migrating PN neurons, which express the receptors Robo1 and Robo2.
Robo2 expression is regulated by the Hox 2 genes, Hoxa2 and Hoxb2. Ventral migration of PN neurons is guided by the ligand Netrin-1 that is released from the midline. The Unc5b receptor is expressed in the dorsal part of the migratory stream A , contributing to maintain the position of r6 derived PN neurons. Hox genes display dorsoventrally nested expression within the migratory stream A Hox5 genes downregulate Unc5b expression in the ventral part of the migratory stream.
But what makes PN neurons migrating rostrally? By the time the PN neurons migrate, most other precerebellar nuclei have already reached their final destination or are in the last phases of migration.
Also, other hindbrain nuclei including the facial motor nucleus FN have already formed. The FN neurons are generated in r4 and migrate tangentially to ventral r6 Garel et al. While their ventral positioning is unaffected, some neurons migrate prematurely towards the midline at ectopic posterior positions. These defects can be rescued by overexpression of Unc5c in PN neurons suggesting a cell-autonomous role Kim and Ackerman, The paralog Unc5b is also expressed in migrating PN neurons, however only in a subset.
The phenotype is reminiscent of the Dcc and Ntn1 knockouts, however without a clear decrease in cell number. The ratio of repulsion vs. Several other factors have been shown to influence PN neuron migration. In mouse mutants for the glycosyltransferase LARGE , the migration is stalled after phase 2 resembling the phenotype in Robo3 mutants Qu et al. Similarly, knockdown of Calmodulin Calm1 resulted in aberrantly positioned PN neurons, and additionally nucleogenesis was affected Kobayashi et al.
Cadherins, a group of adhesion molecules involved in collective cell migration Theveneau and Mayor, , have been shown to regulate the tangential migration of precerebellar neurons Taniguchi et al. Lastly, the meninges are also involved in guiding migrating PN neurons Zhu et al. The chemokine SDF1, ligand of the CXCR4 receptor is released from the meninges and is required for the marginal migration of the PN neurons directly beneath the meninges. Cxcr4 null mutants show multiple ectopic posterior pontine clusters Zhu et al.
Similarly, retinoic acid RA is also released from the meninges and increased RA levels have been suggested to induce defasciculation of the migratory stream and posterior ectopic migration Yamamoto et al. However, due to the extensive effects of varying RA levels on several developmental processes, direct roles in PN guidance are difficult to pinpoint.
Hence, SDF1 might not be the only non-cell-autonomous instructive signal from the meninges contributing to the migration of pontine neurons. But how is the expression of these guidance factors controlled?
Besides the aforementioned transcription factors such as ATOH1 and PAX6, several other transcription factors have been shown to be not only essential for proper migration but also for PN neuron specification. In mutants for the Nuclear Factor Ib Nfib , the PN are greatly reduced and the migration is delayed, suggesting that early migrating PN neurons are more vulnerable to the knockout of Nfib.
However, their targeting to the ventral pons is not disturbed Kumbasar et al. Additionally, genes that are involved in post-transcriptional regulation have been proposed to control migration of precerebellar neurons including the RNA-binding protein Csde1 for the PN Kobayashi et al. The migration of PN neurons from lower rhombic lip to their target region in the ventral pons is followed by nucleogenesis Altman and Bayer, d ; Kawauchi et al.
During this process PN neurons form a 3-dimensional aggregate bulging out of the ventral pons. In mice, PN nucleogenesis occurs between E Various studies done in rodents provide a detailed analysis of the movement of neurons during nucleogenesis; however, the molecular mechanisms involved in the regulation of this process are poorly understood. Timing plays an important role during PN nucleogenesis. Early born-early arriving neurons switch their migration mode from tangential to radial near the ventral midline Watanabe and Murakami, ; Shinohara et al.
Hereby, the soma of these neurons migrates orthogonal to the surface, leaving the leading process behind. The second category is composed of neurons that change their migratory direction without ceasing migration Watanabe and Murakami, In both categories, migrating neurons grow a new short process or a bifurcation of the leading process, enabling the neuron to take up a new migratory route.
This switch between tangential to radial migration is most apparent at E Interestingly, the ability to switch between tangential to radial migration was only seen in early born-early arriving PN neurons Watanabe and Murakami, ; Shinohara et al. Late born PN neurons instead stack ventrally to early arriving neurons Altman and Bayer, d ; Shinohara et al.
Because early born PN neurons are able to migrate dorsally and late born PN neurons are mostly located more ventrally, it was hypothesized that the RTN is populated mostly by early born neurons, whereas BPN is formed of both early and late born PN neurons Altman and Bayer, d ; Shinohara et al.
Migration modes during PN assembly. A Early arrived PN neurons partially migrate radially contributing to the core of the PN, including the neurons of the RTN, or switch their migration laterally below the surface Shinohara et al.
B Late PN neurons rarely migrate radially, but mostly migrate laterally and stack onto progressively forming layers of PN neurons and therefore mainly contribute to the BPN Shinohara et al.
Patterning of the PN during nucleogenesis. A During nucleogenesis, PN neurons populate the target region in an inside-out dorsoventral fashion with early born neurons building the inner core of the PN and late born neurons contributing to the outer shell of the PN. B The rostrocaudal order of PN neuron progenitors at the lower rhombic lip is maintained by postmitotic PN neurons during tangential migration and nucleogenesis.
PN: pontine nuclei, r: rhombomere, pr: pseudo-rhombomere. In addition to the migration along the dorsoventral axis, migrations along the mediolateral and rostrocaudal axes can also be observed during PN nucleogenesis Shinohara et al. Neurons enter the forming PN and migrate medially.
However, some neurons migrate laterally lateral migration , settling at a more distal position, eventually resulting in an expansion of the PN along the mediolateral axis. Both early born and late born PN neuron subsets can switch from medial to lateral migration.
Migration along the rostrocaudal axis of the forming PN occurs rarely and mostly involves early born neurons. In summary, distinct neuron migratory patterns contribute to PN nucleogenesis, expansion and organization. The switch from tangential to radial migration contributes to nucleogenesis along the dorsoventral axis, whereas a switch from medial to lateral migration contributes to mediolateral expansion.
Lastly, widening of the tangential migratory stream has a direct bearing on PN rostrocaudal expansion Shinohara et al. A few studies have investigated the molecular regulation of PN nucleogenesis and the maintenance of PN integrity.
Neph2 null mutants show disrupted intranuclear migration of PN neurons along the mediolateral axis. Most neurons in Neph2 mutant are found to be stuck along the ventral midline.
Barhl1 is expressed in all rhombic lip derivatives except inferior olivary nuclei throughout migration and nucleogenesis. The phenotype of Barhl1 null mutants appears to be mainly due to a postnatal increase in apoptosis Li et al.
However, the downstream mechanisms are still unclear. Even though the vast majority of pontine neurons send their axons to the cerebellar cortex, and are contacted monosynaptically by glutamatergic corticopontine fibers, the information-processing taking place is not well understood.
In addition to typical projection neurons, the pontine nuclei contain putative GABA-ergic interneurons and complex synaptic arrangements. The corticopontine projection is characterized by a precise but highly divergent terminal pattern. Institutional subscriptions support Language. Keep me signed in. Forgot your password? Sign in with Facebook. Sign in with Apple. Description The pontine nuclei are a part of the pons involved in motor activity.
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