Understanding the development of the auditory system is crucial for uncovering the molecular origins of hearing and its related disorders. During this development, spiral ganglion neurons extend peripheral fibers to cochlear hair cells and central projections to the cochlear nuclei, setting up a tonotopic map that connects the ear to the brainstem, enabling frequency-specific sound perception. This sensory information is then integrated bilaterally through a relay involving the superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and the auditory cortex. While anatomical connectivity has been well-documented, recent advancements have revealed gene regulatory networks that coordinate the specification, differentiation, and connectivity of auditory neurons. In this review, we examine the molecular cascades guiding auditory system development, emphasizing transcriptional hierarchies and lineage determinants. Insights into these mechanisms enhance our understanding of auditory circuit formation and provide a critical foundation for therapeutic strategies aimed at addressing congenital and acquired hearing loss.

• Klíčová slova
• Auditory cortex, Brainstem, Cochlear hair cells, Cochlear nuclei, Genetic basis, Spiral ganglion neurons,
• Publikační typ
• časopisecké články MeSH

Auditory processing in mammals begins in the peripheral inner ear and extends to the auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay auditory information via the primary auditory neurons to cochlear nuclei. Information is subsequently processed in the superior olivary complex, lateral lemniscus, and inferior colliculus and projects to the auditory cortex via the medial geniculate body in the thalamus. Recent advances have provided valuable insights into the development and functioning of auditory structures, complementing our understanding of the physiological mechanisms underlying auditory processing. This comprehensive review explores the genetic mechanisms required for auditory system development from the peripheral cochlea to the auditory cortex. We highlight transcription factors and other genes with key recurring and interacting roles in guiding auditory system development and organization. Understanding these gene regulatory networks holds promise for developing novel therapeutic strategies for hearing disorders, benefiting millions globally.

• Klíčová slova
• auditory cortex, cochlea, cochlear nucleus, inferior colliculus, medial geniculate body, superior olivary complex,
• MeSH
• lidé MeSH
• mozek metabolismus   růst a vývoj   MeSH
• sluch * fyziologie   MeSH
• sluchová dráha * fyziologie   MeSH
• sluchové korové centrum metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood. METHODS AND RESULTS: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population. DISCUSSION: Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.

• Klíčová slova
• cardiac sympathetic system, coronary arteries, maternal diabetes, mouse model, sympathetic neurons,
• MeSH
• dítě MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   MeSH
• gestační diabetes * metabolismus   MeSH
• kardiovaskulární nemoci * metabolismus   MeSH
• lidé MeSH
• myokard metabolismus   MeSH
• myši MeSH
• novorozenec MeSH
• srdce MeSH
• srdeční selhání * MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• myši MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.

• Klíčová slova
• auditory behavior, auditory maps, auditory nuclei, inferior colliculus, spiral ganglion neurons,
• MeSH
• ganglion spirale * enzymologie   MeSH
• kochlea embryologie   inervace   MeSH
• myši MeSH
• neurogeneze * genetika   MeSH
• nucleus cochlearis * embryologie   MeSH
• proteiny s homeodoménou LIM * genetika   fyziologie   MeSH
• sluchová dráha * embryologie   MeSH
• transkripční faktory * genetika   fyziologie   MeSH
• vláskové buňky * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• insulin gene enhancer binding protein Isl-1 MeSH Prohlížeč
• proteiny s homeodoménou LIM * MeSH
• transkripční faktory * MeSH