Developmental origin of preBötzinger complex respiratory neurons.
A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the "core" of preBötC SST(+)/NK1R(+)/SST 2a receptor(+) (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST(+) neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R(+)/SST(+) neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. pgray@pcg.wustl.edu
Paul A
PA
Gray
John A
JA
Hayes
Guang Y
GY
Ling
Isabel
I
Llona
Srinivasan
S
Tupal
Maria Cristina D
MC
Picardo
Sarah E
SE
Ross
Tsutomu
T
Hirata
Joshua G
JG
Corbin
Jaime
J
Eugenín
Christopher A
CA
Del Negro
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D017481:Receptors, Somatostatin / Q000235:genetics / Q000502:physiology; D012125:Respiratory Center / Q000166:cytology / Q000187:drug effects / Q000254:growth & development*; D012143:Respiratory Physiological Phenomena / Q000235:genetics; D013004:Somatostatin / Q000378:metabolism / Q000502:physiology
C103403:Dbx1 protein, mouse; D018398:Homeodomain Proteins; D018040:Receptors, Neurokinin-1; D017481:Receptors, Somatostatin; C106140:somatostatin receptor sst2A; D013004:Somatostatin