Molecular Organization and Patterning of the Medulla Oblongata in Health and Disease

Abstract

The medulla oblongata, located in the hindbrain between the pons and the spinal cord, is an important relay center for critical sensory, proprioceptive, and motoric information. It is an evolutionarily highly conserved brain region, both structural and functional, and consists of a multitude of nuclei all involved in different aspects of basic but vital functions. Understanding the functional anatomy and developmental program of this structure can help elucidate potential role(s) of the medulla in neurological disorders. Here, we have described the early molecular patterning of the medulla during murine development, from the fundamental units that structure the very early medullary region into 5 rhombomeres (r7–r11) and 13 different longitudinal progenitor domains, to the neuronal clusters derived from these progenitors that ultimately make-up the different medullary nuclei. By doing so, we developed a schematic overview that can be used to predict the cell-fate of a progenitor group, or pinpoint the progenitor domain of origin of medullary nuclei. This schematic overview can further be used to help in the explanation of medulla-related symptoms of neurodevelopmental disorders, e.g., congenital central hypoventilation syndrome, Wold–Hirschhorn syndrome, Rett syndrome, and Pitt–Hopkins syndrome. Based on the genetic defects seen in these syndromes, we can use our model to predict which medullary nuclei might be affected, which can be used to quickly direct the research into these diseases to the likely affected nuclei.

Transcription factors regulating the specification of brainstem respiratory neurons

“…Depending on the rhombomere, six to eight progenitor domains can be distinguished in the dorsal (also known as the alar plate) aspect of the developing hindbrain, while four to five progenitor domains can be identified in its ventral (or basal) plate (Figure 3). Outstandingly, there exist great resemblance between the developing hindbrain and the spinal cord, in terms of progenitor domains that locate to their dorsal-ventral axis, which share similar gene expression patterns, illustrating common developmental programs that occur between these two nervous system regions (Gray, 2008(Gray, , 2013Di Bonito and Studer, 2017;Hernandez-Miranda et al, 2017a;van der Heijden and Zoghbi, 2020;Diek et al, 2022). In the dorsal-most part of the alar plate, the combinatorial expression of the basic Helix-loop-Helix (bHLH) transcription factor Olig3 with other bHLH genes distinguishes four progenitor domains that give rise to dorsal (d) class A neurons: dA1, dA2, dA3, and dA4 (Figure 3 and Tables 1, 2 for a list of genes expressed in these progenitors and postmitotic neurons) (Muller et al, 2005;Zechner et al, 2007;Liu et al, 2008;Storm et al, 2009).…”

Molecular mechanisms governing development of the hindbrain choroid plexus and auditory projection: A validation of the seminal observations of Wilhelm His

“…The hindbrain rhombomeres and pseudorhombomeres exhibit the same basic pattern of dorsoventral gene expression as the spinal cord (Diek et al, 2022;Hernandez-Miranda et al, 2017;Lai et al, 2016), but with several features that are unique to r0-r7. One example is Wnt gene expression, which shows greater variation in the rhombencephalon than in the spinal cord (Merzdorf and Forecki, 2018), thereby influencing the shape changes associated with IVth ventricle formation.…”

“…Several features of gene expression lead to rhombomere-specific modifications of the dorsal progenitor domains. Ptf1a is expressed in apparent hindbrain-specific duplicate variants (Hernandez-Miranda et al, 2017), a situation that results in an alteration of dorsal cell fates in r0-r7 in Ptfi1a null mice (Diek et al, 2022;Iskusnykh et al, 2016;Lowenstein et al, 2021). Specifically, there is a loss of Neurog1/2 in r1-r6 and a partial loss of Ascl1 in r1-r3 (Hernandez-Miranda et al, 2017).…”

“…The relationship between His' hindbrain regions, modern hindbrain neuromeric organization, the auditory and vestibular nuclear complexes, and the 5 most dorsal progenitor domains. Modified after (Diaz and Glover, 2021;Diek, et al, 2022). important in regulating cerebellar development (Glover et al, 2018;Jahan et al, 2021;Watson et al, 2017).…”

The Role of Neurons in Human Health and Disease

“…It consists of a number of nuclei all involved in different forms of essential and vital activities. Mesman et al [ 4 ] studied the medulla oblongata to identify the progenitor domain of the origin of medullary nuclei to further explore the medulla-related symptoms of neurodevelopmental disorders. Based on the genetic defects seen in these syndromes, they suggest that they can determine which medullary nuclei might be affected and therefore targeted for the therapy of these diseases.…”