Table 4.
Summary of key genes in the development of the principal/projection neurons of the Glutamatergic and GABAergic/Glycinergic lineages of the CN
| Genes with known/suggested role(s) in CN development | |||||
|---|---|---|---|---|---|
| Gene name | Type | Spatial expression in CN | Temporal expression in CN | Expression in other CB cell types | Suggested role |
| Atoh1 | Glutamatergic | Rhombic lip [297] and subpial stream [297] | E9.5 in rhombic lip [297], expression ceases as CN cells migrate within SPS [339] | Granule cells progenitors [296, 297], unipolar brush cell progenitors [340] | Generation of glutamatergic CN [296], specification of glutamatergic lineage [339] |
| Pax6 | Glutamatergic | Rhombic lip and SPS [303, 341] | E13.5 in cells within SPS [303, 341], expression ceases as CN cells enter NTZ | Granule cells [342], unipolar brush cells [341, 340] | Survival of TBR2+ CN [341] |
| Tbr1 | Glutamatergic | NTZ, lateral, interposed, and medial CN [303] | E13.5 as cells enter the NTZ [303, 341], remains in lateral and interposed CN until E16.5 [303], medial CN postnatally [303] | Does not express outside CN in the cerebellum | CN morphogenesis/migration [303] |
| Tbr2 (Eomes) | Glutamatergic | NTZ [303] | E13.5 as cells arrived at the NTZ [303, 341] | Unipolar brush cells [340] | Inconclusive [343] |
| En1/2 | Glutamatergic | NTZ, medial, interposed, and lateral CN [304] | E12.5 in NTZ, maintained in medial, interposed, and lateral CN post-natally [304, 344] |
En1: Purkinje cells, radial glia, granule cells, [344] En2: Purkinje cells, interneurons, unipolar brush cells, granule cells, radial glia [344] |
Survival [304] |
| Lhx9 | Glutamatergic | NTZ, subpial stream, Lateral CN [320] | E10.5 in subpial stream [326] | Does not express outside CN in the cerebellum in mouse | Overexpression in chick lead to re-specify of axon initial trajectory [320]; TBD in mouse |
| Ptf1a | GABAergic/glycinergic | Ventricular zone [295] | E10.5 in VZ [295] | Purkinje cell progenitors, interneurons, and astrocytes [295] | Generation of GABAergic CN [295], specification of GABAergic lineage [339] |
| Sox14 | GABAergic/glycinergic | Nuclear region, Interposed CN, Lateral CN, Nucleus Y of vestibulocerebellar nuclei [160] |
E12.5 in nuclear region between the Pax6+ CN progenitors and Lhx1/5 + Purkinje cell progenitors [160] |
Does not express outside CN in the cerebellum | Migration [160] |
| Genes with spatial information but no identified function in CN development | |||||
| Brn2 (Pou3f2) | Both | Interposed CN, Lateral CN [303] | Region directly above VZ of unknown cell identity[344] | Developmental function for CN unknown | |
| Irx3 | Both | NTZ [341], Interposed CN [321], Lateral CN [321] | E13.5 in NTZ [341] | Not expressed outside CN in the cerebellum | Developmental function for CN unknown |
| Pou3f1 | Glutamatergic | Interposed CN, Lateral CN [321] | E10.5 in SpS, maintained in interposed and lateral CN early postnatal [321] | Not expressed outside CN in the cerebellum | Developmental function for CN unknown |
| Neurog2 | GABAergic /glycinergic | Lateral CN [299] | E10.75 in NTZ [298] | Purkinje cell progenitors, radial glia [299] | CN phenotype not reported in the KO [299] |
| Slc17a6 | Glutamatergic | All nuclei | From E13.5 onward (ABA) | Granule cells; a subset of unipolar brush cells [345] | Developmental function for CN unknown |
| Slc6a5 | Glycinergic | Type 1 and 2 glycinergic or mixed glycinergic/GABAergic (inter-) neurons as described in Table 3; Glycinergic/GABAergic projection neurons in the Med [163] | E13.5 in VZ; CN at E18.5; (ABA) | A subset of glycinergic and mixed glycinergic/GABAergic interneurons of the granule cell layer [306] | Developmental function for CN unknown |
| Pax2 | GABAergic /glycinergic precursors | Only analyzed by scRNA analysis [35] |
So far only documented in adult [35] ABA is equivocal |
(Precursors) of cortical inhibitory interneurons | Developmental function for CN unknown |
| Pax5 | ? | Anterior-medially (ABA) | E13.5 (maybe even earlier) at e15.5, 18.5, p4 very weak signal, potentially in anterior igl (ABA) | Not shown so far | Required for the (early) formation of the cerebellar anlage [346] |
| Ret | Subsets of both glutamatergic and GABAergic/glycinergic cells (Supplementary data [35] at https://github.com/justuskebschull/CNcode_final) | Adult: in all (sub-) nuclei [35, 514] | at least from E11.5 onward (ABA) | Adult: lower ML interneurons; (subset of) granule cell layer interneurons (ABA) | Developmental function for CN unknown |
| Kit | Subsets of both glutamatergic and GABAergic/glycinergic cells (Supplementary data [35] at https://github.com/justuskebschull/CNcode_final) | Adult: in all (sub-) nuclei [35] | from at least E13.5 close to VZ; unambiguously in CN at E18.5; | Inhibitory interneurons of the cb cortex (ABA) [347, 511] | Developmental function for CN unknown |
| Dmbx1 (Otx3) | GABAergic/glycinergic (Supplementary data[35]) | NTZ (ABA), medial, interposed and lateral nuclei [35] | E11.5–E15.5 in NTZ | VZ (ABA) | [348] |
| Lmo3 | Glutamatergic(Supplementary data [35]) | NTZ (ABA), interposed and lateral nuclei [35] | E13–E15.5 in NTZ | Not expressed outside CN in the cerebellum | KO without gross phenotypes [349] |
This table includes genes expressed throughout development: from the proliferative zones (E9.5-E12) to their residency in and around the NTZ (E13-E15), to their final positions in the CN (early postnatal to adult). The table summarizes the seminal papers that identify these cells, their patterns of expression, and their suggested functions. Expression data derived from the Allen Brain Atlas (ABA; https://developingmouse.brain-map.org/). A limited number of genes with spatial information but no identified function in CN development are discussed in the text as they currently offer limited insights into the genetics of CN development